content
stringlengths 27
653k
| pred_label
stringclasses 2
values | pred_score_pos
float64 0.5
1
|
|---|---|---|
Feline corneal diseases: herpesvirus and more (Proceedings)
Feline corneal diseases: herpesvirus and more (Proceedings)
Herpesvirus Infections - Overview
Ocular disease due to feline herpesvirus (FHV) is common. It is estimated that 80% of cats are latently infected with the virus, and approximately 40% of these cats will suffer recrudescent infection in later life. These estimates are based on data that is several decades old, and the actual percentages may be higher. FHV affects cats of all ages, but the initial (or primary) infection usually occurs in neonatal and adolescent cats. Symptoms include bilateral conjunctivitis, respiratory disease, and fever. Most cats recover from the primary infection in 7-10 days without specific antiviral treatment, but neonatal cats are more likely to suffer serious corneal and conjunctival scarring. Recrudescent infection can be unilateral or bilateral and with or without respiratory signs. Unilateral conjunctivitis or ulcerative keratitis in the absence of respiratory signs is common in adult cats with recrudescent infection. Stress appears to be an important factor in precipitating FHV. "Stressful" events may include topical or systemic corticosteroids, concurrent systemic disease, anesthesia, hospitalization, acquisition of a new cat, or extended owner absences (e.g., vacation). Other conditions that may be associated with FHV include non-ulcerative (or stromal) keratitis, conjunctival and corneal scarring (symblepharon), corneal sequestrum, eosinophilic keratitis, keratoconjunctivitis sicca (KCS), blocked nasolacrimal duct, and possibly uveitis. The remainder of this discussion will focus on corneal diseases.
Herpesvirus Keratitis
FHV keratitis can be ulcerative or non-ulcerative, but the ulcerative form is most common and is due to direct cytopathic effects of the virus. The non-ulcerative form (stromal keratitis) is primarily immune-mediated, occurs in response to viral antigen, and is characterized histologically by lymphocytic infiltrates. Corneal ulcers are most often superficial and irregular or geographic (map-like). However, faint linear to tree-branching ulcers, or dendritic ulcers, are considered pathognomonic of FHV. Dendritic ulcers can be detected with fluorescein stain using magnification and a cobalt blue light, but they may be easier to detect using rose Bengal stain. Ulcers resulting from especially virulent strains of FHV, or secondarily infected with bacteria, can quickly deteriorate. Conjunctival graft or corneo-conjunctival transposition surgery may be required for a deep stromal ulcer or descemetocele. Any cat with a corneal ulcer of undetermined cause should be promptly treated with an antiviral agent.
The non-ulcerative or stromal keratitis is characterized by circumcorneal to diffuse stromal opacity and blood vessels. Because the stromal keratitis is immune-mediated, improvement may occur with judicious application of topical steroids. However, topical steroids should be used only if the cornea is negative to fluorescein stain and if prior antiviral treatments have been ineffective. Then, they should only be used in conjunction with an antiviral agent. Caution is advised when contemplating steroid use in a cat with suspected FHV, and frequent examinations (at least initially) are prudent if they are used.
Diagnostic tests such as immunofluorescent antibody (IFA) and polymerase chain reaction (PCR) to detect FHV can be performed on samples obtained by conjunctival or corneal scraping. However, the incidence of false-negative test results is significant. Furthermore, normal cats with no evidence of ocular disease can be positive for FHV. The diagnostic value of such testing is therefore questionable, and the author rarely performs these tests. However, conjunctival or corneal scrapings for cytologic examination can be useful to eliminate other disease conditions from consideration (e.g., eosinophilic keratitis). If a cat has ocular disease consistent with FHV and has not received antiviral treatment, the best approach is to initiate such treatment.
|
__label__1
| 0.90666
|
Modern-Concepts-in-Biology-to-what-a-Plant-is by asafwewe
More Info
Nutriceuticals Workshop
by Florianne Koechlin
Biologist, Blueridge-Institute, Basel - Switzerland
1. Plants communicate
A tomatoe-plant, when attacked by caterpillars, starts defending itself (eg production
of toxins against invaders ) The plant also releases odours to warn neighboring
plants so they start their self-defense. The odour is known to be a mixture of methyl-
jasmonates (also used in perfumes).
Triangle maize – caterpillar parasitic whasp : Experiments by Ted Turlings, University
Neuchatel (CH) show that when maize is attacked by caterpillars, little whasps
(Spdoptera Exigua Hübner) arrive soon and parasite the caterpillar. The plant sends
out „SOS-signals“ to attract the whasps. The plant „tastes“ the presence of caterpillar
by a molecule (volicitin) in their saliva and then starts to produce the SOS-signal – a
flexible triangle. (T.Turlings and B.Benrey, 1998, Ecoscience, 5 (3), 321)
„Communication“ among plants with the help of scent-molecules is common („a
constant chattering“)
2. Plants react to at least 16 parameters from the environment.
Plants can sense light, temperature, gravitiy, movement, chemicals etc. They react
to these parameters, change their behaviour accordingly (such as growth, number of
leaves, thickness of stem).
3. Plants „learn“ through trial and error
The overall goal is to maximise fitness in an unpredictable, ever changing and
extremely complex environment.
Example: Rootsystems must make decisions about growth, direction, dephts,
avoiding competing roots etc. They must integrate signals of soil hardness , stones,
light penetration, temperature, insects and microbes, distribution of water, Calcium
and niotrate, presence of gases such as CO2 etc; they compute these signals
together with many internal ones into decisions which are necessary for root-growth.
(A.Trewavas, 2004, Annals of Botany 93, 353)
4. Plants have a “memory“
Animal memory is often defined as: The experience of one organ can be used to the
advantage of others. Such processes are also known for plants.
Example: The pre-exposure of roots of a growing plant to low levels of salt or to
dryness enables the plant to survive later in normally lethal concentrations of salt or
in draught. The experience of the roots is thus translated to the whole plant. Pre-
treatment learning can last months or years, it also can be interrupted if the
conditions are reversed. (A.Trewavas, 2004, Annals of Botany 93, 353)
5. Are plants „intelligent“?
Anthony Trewavas (University Edinburg, GB) thinks so: Among the many definitions
for „intelligence“ he chooses the one given by David Stenhouse (philosopher and
psychologist from New Zealand): „adaptive and flexible behaviour during the lifetime
of an individual“. This is what plants are doing: they show a flexible, adaptive – and
most important: not all-predetermined – behaviour (although their behaviour changes
might be small and slow)
Example: Cuscuta, a parasitic plant which sucks the juice of its hosts: Cuscuta
comes to a hostplant and checks first, if it is worthwhile. If not: it moves on., If yes: it
starts building coils around the host. Cuscuta also computes if the host is a good one
or not: Many coils around a good one, few coils around a meager one. Amazing fact:
from the first encounter to the point where Cuscuta gets to juice and nutrients from
the host there is a timelaps of 4 days. Cuscuta computes the outcome 4 days in
advance and reacts accordingly. This, Trewavas concludes, is intelligent behaviour.
Studies show, that the molecular basis of learning in animals and in plants is very
similar (eg equal or similar signal pathways )
But where is the brain? Probably it is the whole plant, probably the membranes of
cellplasma, where hundreds of signal-molecules are located . It’s probably there
where most of the interactions and computing is done.
6. Differences between plants and animals
Animals move, plants are sessile.
Plants show an open organisation, a modular growth; they are „meta-populations“
Each organ is quite independent of the others. You can cut branches from a tree, you
cannot cut legs from an animal. Development and growth of animals means
development of an individual. Development and growth of plants means adding new
members (eg leaves, roots), getting rid of others. Plants consist of ever changing
Both plants and animals show much flexibility to optimise their fitness. And Trewavas
adds: „Intelligence“ in our culture is always defined in relation to action: Animals must
be fast, flee or attack. But plants do not move fast, they donot appear to be clever.
Their flexible behaviour may show within hours or days.
7. Conclusions
Not: Stop eating salade....But perhaps this radical new scientific view of what a plant
is might help change our perception of plants, might help argue against transgenic
plants, terminator and patents on plants. It also opens new and exciting perspectives
for agriculture (eg use of odours, enhancing induced self-resistence etc)
Article 24 of the Swiss constitution prescribes that the „dignity of creature“ has to be
guarded. Are plants creatures? If Yes, what are the implications? The Swiss Ethics
Committee EKAH (of which I’m a member) will discuss this issue in near future.
To top
|
__label__1
| 0.988886
|
Tsim Sha Tsui
Restaurants in Tsim Sha Tsui
The über-chic modern dining room and towering, panoramic harbor views are stunning, but the cuisine—half Japanese, half Italian—is just as bold, with a structural integrity that gives the vistas a run for their money.
The famous Longjing tea leaves from the Hangzhou region make the stir-fried freshwater shrimp taste sweet and earthy, but the star of the show is missing from the English side of the menu—the smoked yellow croaker, an unremarkable, bottom-dwelling creature that, in the hands of the Tin Heung Lau
A team of Japanese chefs prepare robatayaki, or grilled meats and seafood, in this atmospheric, lantern-lit restaurant, located ina 19th-century lighthouse. Standouts include Yamaguchi chicken, Kagoshima pork, and Australian Wagyu sirloin skewers.
|
__label__1
| 0.978386
|
Drum Fill Friday: Classical Headbanging Edition
Try to identify the classical pieces that spotlight the timpani (kettledrums), bass and snare drums. Score high and hurl your imaginary sticks into the roaring audience. Score low and kick yourself, not your bass drum.
While you might think that advertising a classical music quiz with a photo of Led Zeppelin drummer John Bonham is a mistake ... BOOM! You'll see why he's there in the very first question.
|
__label__1
| 0.985678
|
Judge John Durkin
Mahoning judges explain 'backlog'
The five Mahoning County Common Pleas judges said criminal and civil case filings are at an all-time high, making it impossible for them to …
Weathersfield police
Possible police imposter sought
County records damaged
Heavy rain damages records
|
__label__1
| 0.999947
|
Corey Lee decided to open a modern bistro in Hayes Valley for several reasons, but the main one comes from his own perspective as a diner.
The way he sees it, there isn't one restaurant doing all the things that a great modern bistro does: neighborhood friendly, serving creative bistro fare and, particularly important to chefs working long hours, open late.
That's what Lee - chef/owner of Benu, the four-star SoMa fine dining destination - hopes to give San Francisco when he opens his second restaurant, Monsieur Benjamin (451 Gough St.) in the spring.
"We have some great late-night dining in San Francisco, but there are only a few of them," Lee says, adding that he was also looking for more traditional French cuisine, but updated with seasonal ingredients and modern techniques.
The trick, he says, is to do that while keeping the hallmarks of a great bistro - designed for everyday dining, comfortable, bustling, casual.
"It's this living breathing genre," Lee says. "But when it's been translated to the States, in an attempt to convey authenticity, the modernization is gone."
The chef will be Jason Berthold, last seen at RN74 and a former colleague of Lee's at the French Laundry and Per Se. Berthold will work closely with Lee and Benu chef de cuisine Brandon Rodgers on the opening menu, but Monsieur Benjamin will be Berthold's kitchen to run.
San Francisco's Aidlin Darling Design will design the 95-seat space, with the same approach that Lee and Berthold are taking with the food - maintaining classic bistro reference points while updating the genre.
And how about that name?
"It's a name I heard when I was in Paris," Lee says, explaining that the two words next to each other conjure up a French-American juxtaposition that flows nicely.
"I have no idea who this person was, but it was an American. And it sounded right."
Going West: With an award-winning design, 25 Lusk was one of the biggest and flashiest openings of 2010. Now the ownership duo of chef Matthew Dolan and general manager Chad Bourdon are plotting a second restaurant.
They're working on a new place on the top floor of the Westfield San Francisco Centre (865 Market St.) alongside Martin Yan's M.Y. China, Cupola and Lark Creek Steak.
Bourdan says the unnamed 5,000-square-foot project is still in the development stage, but that it will be different from the polished, upscale 25 Lusk. Instead, this new place will be more approachable and lunch-friendly - and likely have some technology components.
"Conceptually, we have a strong idea," says Bourdan. "But we're working within the parameters of what Westfield wants to see, so some details are pending."
Going for gold: The American team in the 2015 Bocuse d'Or, a competition that has been likened to the culinary Olympics, will have a local flavor.
Philip Tessier, executive sous chef at the French Laundry for the past three years, has been selected to represent Team USA; his commis (or assistant) is 21-year-old Skylar Stover, also of the French Laundry.
The Bocuse d'Or, held every two years in Lyon, France, has traditionally seen the Americans taking a back seat to their European counterparts. In this year's competition, West Virginia's Richard Rosendale finished a disappointing seventh.
But maybe the restaurant lineage will do the trick: The highest-finishing American ever is Timothy Hollingsworth, who placed sixth in 2009 and also came from the French Laundry system.
Fresh squeeze: Mission District anchor Foreign Cinema (2534 Mission St.) has a new face behind the bar - and, for that matter, an entirely new bar.
Chefs/owners Gayle Pirie and John Clark have remodeled the restaurant's bar, and given the new look, it made sense to refresh the rest.
Kevin Dowell - a vet of Zero Zero, Wo Hing and Laszlo - has been appointed bar manager and is creating new cocktail menus for dinner and brunch. The new lineup is set to debut Jan. 2.
When diners go wild: There is a special circle of hell reserved for those diners that steal things from the restaurants they are patronizing. Sometimes, though, they get their just desserts.
Tyler Florence, who owns Mill Valley's El Paseo and San Francisco's Wayfare Tavern, recently shared one such tale on Instagram.
On Saturday night, Mill Valley police pulled over a car for a traffic violation. When the driver was searched, he was found to have a pair of El Paseo steak knives hidden in his socks.
A police officer returned the knives to their rightful home.
|
__label__1
| 0.753706
|
Difference Between Single Pole and Double Pole Switches
Double pole switches control two circuits at the same time.
Switches of the type you use in your house have existed since around the same time as the invention of the light bulb. A simple wall switch for an individual light, called a single pole switch, controls only one circuit. A double pole switch, on the other hand, controls two. Its most common application involves controlling 240-volt circuits, such as the one powering your furnace, which have two separate 120-volt lines.
Thomas Edison usually receives credit for the invention of the light bulb, but Joseph Swan actually simultaneously invented a light bulb in England in 1878. Edison unsuccessfully sued Swan for patent infringement, but they later formed a partnership called the Edison-Swan Electric Company. As Newcastle became one of the first cities lit by electricity, the need for a method to quickly disconnect the new light bulbs became apparent. J. H. Holmes of Newcastle filled this need by inventing the first quick disconnect switch in 1874. His company, the Newcastle Electric Works, manufactured the switches.
The number of connections, or throws, switches can make and the number of wires, or poles, they can control determine their classification. The common single pole, single throw (SPST) switch has only one position besides “Off” and has only one pair of wires. An “On/Off” switch for a 240-volt circuit, on the other hand, is a double pole, single throw (DPST) switch because it controls the two 120-volt hot wires in the circuit simultaneously. You would need a single pole, double throw (SPDT) switch to control two lights independently of each other.
An SPST switch has two hot terminals to which you connect the wires coming from the circuit and going to the fixture you want to control. In the most common form, a lever, easily controllable with your finger, toggles the rocker arm inside to the switch to make contact between the terminals when in the “On” position. A DPST switch functions like two of these joined together. It has four terminals, two for each circuit, and connects them simultaneously when you flip the lever to the “On” position.
Double pole switches basically represent larger versions of single pole ones, making it difficult to tell them apart. The best way to identify a double pole switch is to note that it has four brass terminals instead of two. To make the identification of double pole switches foolproof, manufacturers use green plastic to encase them, instead of the white plastic they use for single pole switches. Except for these two differences, the switches look almost identical. They do not differ significantly in size, and each has a green ground screw on the bottom.
To install a switch in a 240-volt circuit, you need a double pole switch. Possible applications in your house include the furnace, air conditioner or a hot tub. You can also use a double pole switch to control two different light circuits simultaneously and save yourself the inconvenience of installing two separate switches. A double pole switch confers an advantage if you have multiple lights or outlets to control in a room but limited space for electrical boxes. Disadvantages include the fact that both lights or fixtures connected to the switch will always have to come on at the same time.
|
__label__1
| 0.828806
|
Warning message
About NIA
Fiscal Year 2002 Budget
Older Americans are generally better off—healthier and wealthier—than ever before.1 Average life expectancy in the United States has at least doubled over the past century, and a baby born today is expected to live almost 30 years longer than one born in the year 1900. These improvements in life expectancy, from an average of 49 years in 1900 to age 76 at the turn of the 21st century, plus the advent of such programs as Medicare and Social Security have helped to improve both the physical and fiscal well-being of the Nation's older population. The added years of life have allowed the vast majority of older Americans to enjoy a healthy and active retirement. A majority of people 65 and older rate their health as good or excellent.
But good health is far from a universal reality for older Americans. The latest national surveys indicate that about one-fifth of people age 65 and older, more than 7 million people, report some disability.2
Chronic disease, memory impairment, and depressive symptoms affect large numbers of older people and the risk of such problems significantly rises with age. Nearly half of those age 85 and older suffer from Alzheimer's disease.3These millions of less fortunate older people struggle with daily activities as simple as bathing and dressing, with families and friends taking on the difficult and often costly role of caregiver.
Understanding the difference between advanced years that are active and independent and those that are characterized by frailty and dependence is at the heart of the NIA's research program. Since the Institute's founding in 1974, research has shed considerable light on aging and health.It is now known that aging itself is not the cause of disease, disability, and frailty associated with advancing age. Indeed, the converse is true: It is disease and disabling processes, influenced by age-related changes in the body and by unhealthy choices and sedentary lifestyles, that are the most important factors in compromising the quality of life for older people. This fundamental shift in thinking was reinforced most recently with insights from the National Long Term Care Survey (NLTCS) and other such longitudinal analyses. According to the NLTCS, the rate of disability among older Americans dramatically declined from the 1980s through the mid 1990s, even among people age 85 and older, who are most vulnerable to disabling conditions. These findings, along with evidence from a number of clinical trials and studies testing specific interventions, suggest more strongly than ever that disease and disability can be addressed and are not inevitable consequences of aging.
The challenge now is to maintain and even accelerate the trend in declining disability and to reduce rates of disease amid a steep rise in the number and proportion of older people. The task is urgent. Demographic projections show that the U.S. population is beginning to age at a rapid pace, with the first baby boomers turning 65 in 2011. Between now and the year 2030, the number of individuals age 65 and older likely will double, reaching 70.3 million and comprising a larger proportion of the entire population, up from 13% today to 20% in 2030.4 Of great interest is the explosive growth anticipated among those most at risk of disease and disability, people aged 85 and older. Their ranks are expected to grow from 4.3 million (1.6%) in 2000, to at least 19.4 million (4.8%) in 2050.3 The racial and ethnic makeup of the older population will change dramatically as well, bringing with it possibly even greater racial and ethnic disparities in health among a more diverse population of older Americans. These demographic factors threaten to combine to increase the burden of age-related diseases and conditions on individuals, families, and society. Unless new understandings and interventions are developed and implemented to reduce disease and disability before the population ages so intensively, the costs, in both human and financial terms, could be extraordinary.
In the 20th century, health research and public health practices did much to extend life and improve health. At the start of this new millennium, the NIA's research portfolio is aimed primarily at increasing "healthspan," or years of healthy active life expectancy. Aging research is at the threshold of discovery,poised to build upon the work of recent years to make a difference in the lives of older Americans and their families. Toward that end, NIA's overall program is wide-ranging and includes research on: the biochemical, genetic, and physiological mechanisms of aging in humans and animal models; the structure and function of the aging nervous system; social and behavioral aspects of aging processes and the place of older people in society; and the pathophysiology, diagnosis, treatment, and prevention of age-related diseases, degenerative conditions, and disabilities. The NIA is the lead federal agency for Alzheimer's disease research.
In close collaboration with the National Advisory Council on Aging and other public and private organizations, the NIA has developed a strategic plan for aging research, to identify goals for the next 5 years. These goals address scientific areas that hold the greatest promise for advancing knowledge, many outlined in this narrative. The NIA also recently completed a strategic plan on disparities in health status of older Americans of different racial and ethnic backgrounds. In this narrative, the Institute focuses on recent progress and future directions for research in four key areas: Section I.) Alzheimer's disease and the neuroscience of aging; Section II.) reducing chronic disease and disability; Section III.) the biology of aging; and Section IV.) the behavioral and social aspects of growing older. In each of these efforts and more broadly, the Institute is paying special attention to reducing health disparities among different groups of Americans (Section V.). Interspersed within the narrative, in two sections, are "Stories of Discovery," which follow the history and the drama of unfolding scientific knowledge in a specific area of interest.
2. Manton KG, Corder LS, Stallard E. Chronic disability trends in elderly United States populations: 1982-1994. Proc Nat Acad Sci USA 94: 2593-2598, 1997.
3. Evans DA, Funkenstein HH, Albert MS, et al. Prevalence of Alzheimer's disease in a community population of older persons; higher than previously reported. JAMA 262: 2551-2556, 1989.
|
__label__1
| 0.963178
|
Muppet Lessons
Breaking down the resolutions of three specific conflicts over the course of the “Classic Muppet years,” this article reveals examples for anyone attempting to preserve their art while also making money.
“…The lesson to take away from Henson’s management style is to freely and honestly give no for an answer, to listen well and then say it calmly but firmly, to protect the quality of your work. Three conflicts and three resolutions. This is a lesson for Disney—as it goes forward with Muppet films—and for any creative entrepreneur, anyone interested in making (good) art pay.”
|
__label__1
| 0.998608
|
Chef Pankaj Ka Zayka Episode No. 19
Chef Pankaj welcomes her mentor and friend, Chef Kunal Kapoor to an exciting episode of Chef Pankaj Ka Zayka. Chef Kunal prepares a tasty and poetic Daastane Paneer and a delectable Gulaab Jamun cheese cake for dessert.
kunal kapoor
Hrithik, Aishwarya, Abhishek at Kunal-Naina’s wedding reception
Kunal Kapoor, Naina Bachchan to host wedding reception in Delhi
Inside Aamir Khan’s grand birthday: Ambanis, B-town in presence
Perfectionist Aamir Khan’s lavish birthday bash was a starry affair. The actor’s producer wife Kiran Rao threw a grand 50th birthday at Lonavala. A day before the birthday Aamir Khan celebrated birthday with media by cutting veg cake and interacting with the media. The birthday was thr
|
__label__1
| 0.845655
|
Genesee Community College
Quick Links
Genesee Course Catalog
Official Course Information
Fall 2012
Physical Therapist Assistant Courses:
or List All Physical Therapist Assistant Courses
PTA106 - Physical Therapy Assistant Seminar 1
Credits: 2
Catalog Description: Introduces interpersonal skills and professionalism relevant to the health care environment. Addresses interactions between PTA and patients, therapists, and other health care team members. Advances concepts of social and cultural competency, confidentiality, and professional responsibilities. Addresses state laws and professional therapy association positions and their integration into clinical policies and procedures. Covers computer literacy, on-line medical research, effective study skills, and continuing professional development. Prerequisite: Acceptance into the PTA program. Corequisite: PTA 101.
Lecture: 2 hrs.
Course Student Learning Outcomes (CSLOs):
1. Demonstrate basic verbal and non-verbal communication skills with patients as well as other health care providers through participation in 3 situational role play presentations.
2. Demonstrate basic computer literacy through completion of 4 on-line assignments and participation in at least 4 on-line discussions.
3. List 4 examples of patient interactions which may be impacted by cultural or socioeconomic differences and in writing or during a role play, suggest appropriate modifications to address these issues.*
4. Demonstrate good study habits and time and stress management techniques through the written analysis of student's own study and lifestyle habits as well as written and oral discussion of areas in which change is required.
5. Identify at least 2 basic principles in each of the following areas: levels of authority, professionalism, planning, supervisory processes, performance evaluations, fiscal considerations, and clinical policies and procedures and discuss their importance in both written and class discussion formats.
6. Discuss in writing and orally 3 ways in which patient and family interactions are affected in each of the following areas: geriatrics, pediatrics, and while working with patients with disabilities.
7. Give 3 examples in writing which illustrate the changing face of physical therapy as it pertains to alternative medicine as well as patient education.
8. Write a research paper accessing health care literature via electronic sources (Internet and on-line journals) as well as hard copy resources.
9. List 5 important dates in the development of Physical Therapy in the US and discuss the significance of each.
10. Discuss the role of the PTA in terms of the history of the profession as well as identify supervision levels in acute care, SNF, home care and pediatric settings as per the NYS Practice Act.
11. List 5 significant dates in the history of the American Physical Therapy Association and discuss each date's significance. Discuss national, state and district APTA organization and the APTA's role in the oversight of the physical therapy profession.
12. Define in writing managed care and at least 5 related terms and discuss its impact on the healthcare system in the US today from the patient's and health care provider's points of view.
13. Describe in writing and role play the multidisciplinary team concept and discuss 3 reasons why it is important in health care today.
Content Outline:
I. PTA Education, Role and History of PTA, Learning Process, and
II. Accessing Information, computer technology and
Evidence Based physical therapy
III. Communication and Professionalism
IV. Ethics, Diversity, and Cultural Competency
Effective Term: Fall 2012
|
__label__1
| 0.659607
|
Ethanol subsidies continue to take punch after punch in the ring of public opinion. This time it’s the Washington Postthat is getting in on the action.
A staff editorial appeared in Tuesday’s edition of the Post, which pointed out that no matter the reason the subsidies continue to survive, they must end. “The supports must go. Congress has protected ethanol three ways: with a $6 billion-a-year tax subsidy to those who blend it into gasoline, a tariff on competing imports and a mandate that billions of gallons enter Americans’ fuel tanks every year, which come on top of three decades of federal patronage of the industry.”
As the piece goes on, the Post points out there are still ways the subsidies could survive. “Ethanol still seems to have hope in Washington. Somehow, some conservatives are wary of repealing the fuel’s tax subsidies because they could be construed as tax increases,” says the editorial.
In recent weeks ethanol subsidies have continued to survive on shaky ground. In June, the Senate voted to remove the $6 billion handout to the industry by a very wide margin. But because that amendment was attached to another bill that failed passage, the subsidies lived for another day. Most think the subsidies have little hope of surviving the chopping block during the upcoming debt ceiling debate. But factors like the Iowa caucus, fears about eliminating the handout being construed as a tax hike, and the idea that cutting this could lead to the end of oil subsidies have made getting rid of ethanol subsidies harder than it should be.
If ethanol subsidies survive another round, it certainly will because of special interests and straight-up politics, not because of a lack of outcry from major media outlets.
|
__label__1
| 0.993697
|
Thursday, June 24, 2010
Pinchas (Cozbi and Zimri)
This week I am cheating and using an old poem that I had written which will appear in the upcoming edition of the Mima'amakim journal this fall. It is an off-kilter sonnet voicing my discomfort with the massacre of Cozbi and Zimri by Pinchas. Viewed allegorically, much like the conquering of Eretz Israel in the book of Joshua, I have no problem with this narrative. These heroic though violent figures are extirpating the negative aspects of their own personalities and those within our communities. They are doing a reparation, a tikkun, by destroying the impulses that drive our animal soul.
Well, that works on a figurative, Kabbalistic level, but if we view Torah as a living history, how can one reconcile murder in the name of G-d? On top of that, Pinchas, a Kohen, is rewarded by HaKadosh Baruch Hu. In an age, in this way similar to all others, in which fundamentalists claim the right to exercise violent action based on divine authority (think Taliban, Saudi Arabia, GW's holy war which we continue to wage in the Middle East, Homophobes sanctioning hate crimes, a handful of militant Zionist settlers--NOT the Israeli majority-- who continue to decimate certain Arab populations because they believe it to be the will of G-d) and it becomes an even more frightening contemporary issue.
Please forgive me for getting so political for a moment, but this poem presents my, perhaps all too American, fear of what happens when religion and politics, or religious and political power become too much intertwined. Granted, I understand that there is a political vision presented by the Torah; however, that vision is not only political but spiritual. The just society that we will finally enjoy in the time of Mashiach will create an environment in which every person will have their material needs met, live in temporal and physical ease so that we can spend all our time connecting with the Divine. Perhaps Pinchas, though overly zealous, represents the singleminded person who only lives for that future time of redemption and his real shortcoming is wanting a future reality of justice so much, that he is willing to sacrifice the here and now, i.e. his relationship to those still created in G-d's image who do not share this vision. Who knows. Please enjoy and I welcome and encourage your thoughts and comments on the poem, or the politics...I guess.
Shabbat Shalom!
Cozbi and Zimri (in memoriam)
A sharp removal: triceps return flesh,
Burgundy triangle lance dances slow
Above the broken vessels—seeping thresh.
Pinchas ruffles his priestly brow, eyes low.
How can those holy fingers elevate
After slicing through missteps of the dead—
Cozbi, a woman who germinates bait,
Easily bitten off by the prince, red—
Weak. Night quivers, like a bonfire’s embers.
Broken bottles, casks, grapes in the dirt,
Swallowed by earth, preserved in the amber
Like mosquitoes, ink on parchment—inert.
Pinchas, we dance through raw desert, lovesick—
Our shipwrecked race...yet, a reward for this?
Coming Soon!
Coming Soon!
Beha'alotcha (Wicks in the Wind)
I am indebted to a connection pointed out to us at Yeshivat Hadar by my teacher, the brilliant Dr. Devorah Steinmetz. In her literary approach to the narratives of our tradition, Dr. Steinmetz pointed out that the use of the word matar in most instances in the Torah are a type of punitive dew or rain. That is, something Ha---Shem sends as a punishment for haughtiness or some other infraction committed on either divine kingship or, in modern parlance, the categorical imperative.
Using this as my starting point, I've constructed a poem as a dialogue between Ha--Shem and B'nei Israel with HaShem instructing us to be holy, to keep moving toward Him and evolving, and with us kvetching about our material needs and dwelling in the constricted and limiting idealization of a past reality, rather than embracing this moment. B'nei Israel have a ball recalling all that was so glorious in Egypt, but, as Proust reminds us in his A la recherche du temps perdu memories are hardly ever authentic or truthful. A spiritual teaching that I have always sought to embrace is that this moment is really all that has significance and our halacha, whether obviously or not, imputes this message as much as any other.
Shabbat Shalom!
Beha’alotcha (Wicks in the Wind)
G-d: in your making go up,
into clouded cover,
night fire.
It’s all but a parochet,
a veil,
to tear through.
It’s all but a
To tear through,
To seduce Me.
Rest as wick; I’ll be your oil.
Stand wax still
O ye vessels
For My flame—
Spots for My sun.
B’nei Israel: Great…but who might feed us meat?
zacharnu et-ha eating!
Gah-gah-gah garlic, free-fish,
Cucumbers encumber mind’s eye in
Watermelon leaking leeks,
Hills of coriander seed.
Let’s grind it in a mill
like oil cake
drenched in morning dew.
G-d: Wicks in the wind!
Wicks in the wind!
If not... I’ll damn you in dew.
Shelach Lecha (The Woodgatherer)
I often find myself struck by the starkness of the biblical narrative. In Erich Auerbach's seminal work Mimesis: The Representation of Reality in Western Literature, the German-Jewish literary theorist and critic notes the salient difference between the detail of motives and description of action in Greek epic on the one hand, and the vague hyper laconism of the bible on the other. Auerbach attributes this distinction to the purposes set forth by the two texts; that is to say that the Greek epics were originally oral works open to the poet to embellish, but wholly a work of entertainment. Granted, one can glean moral teachings from Achilles' modus operandi in battle situations, or Ulysses journeying back to Ithaca, but the real meaning lie in those texts presenting a rubric from which the talented poet could improvise for the enjoyment of his spectators.
The Bible, on the other hand, is a legal text interspersed with narratives that expound the laws contained herein.
This idea, astute and yet somewhat obvious as it is, has never helped me to fully connect with biblical narrative. But it was also one of the catalysts for my undertaking the project of poem ha-shavua. What is interesting, at least artistically, about what the Torah is not saying? How are these figures thinking in the time of narrative, existential, and spiritual strife? As far as I am concerned, it is within the silence of biblical personages (our ancestors, paradigms of righteous and errant ways) where we find the Torah's true meaning. It is in the inscrutability or occasional unjust nature of things that happen that truly teach Jews and the Umot Ha-Olam how to live. That is because, quite simply, these moments where something happens and we have no idea of a personage's thoughts in that moment require us to ask ourselves "why," and search for the answers whether we find them or not. Perhaps this is the greatest gift of our sages in the Talmud when they expound upon our tradition with discourse and more than a few "Frank" interrogative terms.
This week's parashah is a wonderful and somewhat disturbing example of this economical narrative that forces us to drash as much as we can. The mekoshesh etzim "woodgatherer" punished for collecting wood on Shabbat. We ask might ask ourselves if he knew it was indeed Shabbat, or if he had been a tzaddik or malach simply
doing G-d's will in order that G-d could teach Moshe and B'nei Israel how to punish someone for transgressing the Shabbat.
All of these questions and many more are addressed in the commentaries. However, in my poem this week, I used the example of the woodgatherer as a meditation of the nature of Shabbos. Is it an ontological reality that we simply acknowledge and observe, or rather is it something that we must build or do (as the Torah reads with la'asot et ha Shabbat) with no intrinsic value beyond our spiritual striving? Could the woodgatherer feel the presence of Shabbat, or was he simply disobeying G-d without any repercussions but for his later punsihment?
I hope you enjoy this poem. I have fallen behind in this endeavor but hope, B''H, to be caught up in the next couple weeks. Please keep checking in. Shabbat Shalom!
Shlach lecha (The Woodgatherer)
Is there indeed a difference in the way
this lumber wilts,
my withered
unlike other days,
each pile
I make slides to a pool… an ocean… submerging
my blackened feet…a wave of wood… the jellyfish smart—
of stones.
Coming Soon!
|
__label__1
| 0.916515
|
Sponsored Links
Advertise Here (More Info)
Get your Master Numerology Reading
The 11 Forgotten laws
Stock Photos Wanted
Build a Better Mind
The Secret of Deliberate Creation
Free Usui Reiki 1 Course
Advertise Here (More Info)
Joy happens within the moment. Joy activates the soul. True joy comes from following the higher purpose of your soul. Joy is something you experience now. If you feel there are reasons why you can’t experience joy right now, begin to create reasons why you can. If you're looking to the future to allow joy into your life, it may always remain just out of your reach.
Joy radiates from the center of your being. If you're looking outside yourself for joy, you will not find it. You won’t find joy in any situation that enslaves you to outer outcomes and situations.
Emotional Freedom is the Key to Experiencing Joy
It is usually emotions that snare you into joyless situations. That is why the key to experiencing joy is emotional freedom. If you find yourself in any situation or relationship that is not bringing you joy, it’s time to examine your beliefs. You will want to look closely to see if you hold any beliefs that say you must do anything that doesn't bring you joy. Often, when you look deeply into circumstances devoid of joy, you find that at the root the belief that you believe you don't deserve joy.
As a Divine being, your birthright is all the love, abundance and joy the universe has to offer. If you believe otherwise, it’s time to transform these beliefs to bring them into alignment with the Divine perfection of your spirit.
You're not obligated to do anything that doesn’t bring you joy. You’re not obligated to spend time with those who drain your energy, dishonor or disrespect you. As a Divine being, you can look at each person through the eyes of spirit and see what, if anything, you can do to help heal or assist them. If a person insists on remaining in a negative feeling state, you don’t have to allow them to pull down your energy. It is never for your highest good or that of another to lower your resonance in this way.
Focus on the Blessings in Your Life
Spend time appreciating what you have, noticing the moments of small blessings as you go through your day. Nature is a portal into joy. Notice flowers and sky. Notice the full moon through the trees. Notice night sounds in the woods. Notice the way the sun radiates off the surface of water.
Notice where you place your attention. Where do you put your time, energy and focus? It’s important to spend time in ways that help you in realize your highest good.
Create a ‘Joy’ List
Make a list of what you love, what brings you joy. What you love is directly linked to your spiritual purpose. The things on your joy list that you feel most drawn to right now represent steps you can take in your present moment to fulfill your spiritual purpose. As you take these steps, the path unfolds before you. In this sense, all roads lead to the same place. Don’t be concerned with what you "must" do now. Allow your journey to be a joyful dance with spirit as you allow each moment to unfold its own beauty and perfection.
Scarcity Consciousness and Joylessness Go Hand in Hand
If you resist doing what you feel most drawn to within the moment, if you resist doing what brings you joy right now, you're pushing away the feeling state of joy and the abundance that naturally flows through this doorway. Ironically, many resist doing what is most joyful to them because they are enslaved by thoughtforms that they must work hard at joyless occupations to manifest abundance. By denying joy, they push away the abundance they are seeking!
Every moment of every day you're receiving "cues" from your environment of the next step you can take on your journey of self-realization and joy. Begin each day by asking yourself what you can do that brings you joy. Give yourself permission to act on the answers. As you place your focus on joy, you will naturally know how to handle any challenges that come before you. When you're in a state of joy, your energy field is open and flowing. Information, guidance and life force energy pulses through you. You are open and receptive to guidance and feelings of well-being.
Many of you have settled for what passes for joy in your life, feeling it is impossible for you to be truly joyful. You will always find this circumstance disappointing. You will only have true joy in your life when you bring your focus to allowing it. Don't settle for anything less than this no matter what is going on around you.
Merging with Your Spiritual Purpose
You don't have to know the specifics of your spiritual purpose. It is enough to set an intention to align with your purpose for this lifetime. See this intention entering the cells of your body. Align your energy and your resources with your spiritual purpose. In time, you will begin to make different decisions in how you spend your time. As you take steps based on your intention to follow your spiritual purpose, it will begin to take form in your life. You'll find yourself drawn to new people, situations and ideas.
Joy is Self-Love and Appreciation
This is where you begin to act through joy - to choose and do things based on the joy they bring you. As you explore all the things that bring you joy, you come face-to-face with your spiritual purpose. If you're not sure of your exact purpose, just begin doing what brings you joy and you will soon find it.
Begin each day by affirming it is another glorious opportunity to experience joy. Hone your gifts and talents and share these with others. This is another day to step into the unlimited abundance of spirit. Having a goal and purpose for everything you do allows you to examine each proposed activity to see if it adds meaning and joy to your life or if it is just another empty, meaningless activity void of fulfillment. Observe if what others are asking of you is for your highest and best and for theirs. Examine if staying at a job that has grown stale is for your highest good. Learn to read the subtext of your life. By staying at a job where you feel in undervalued and unappreciated, you are affirming it is the same as saying you're not worthy of anything better, that you are in effect the one doing the undervaluing and under appreciating, and others are simply mirroring this to you.
Ways to cultivate the path of joy in your life:
One) spend time in nature
Two) notice where you place your focus and attention
Three) create a joy list
Four) focus on the blessings in your life
Five) create emotional freedom. End self-sabotage
Eight) be here now
Nine) practice discernment with others
10) read the subtext of your actions to learn any ways you are buying into scarcity
11) build a new vision for your life
12) align with your spiritual purpose
promote this teaching, get code
Top Videos
More from this user
|
__label__1
| 0.724822
|
Older Adults Make Smarter Decisions That Lead to Long-Term Gains, Study Shows
Many people believe getting older means losing a mental edge, leading to poor decision-making, but a new study from psychologists at The University of Texas at Austin and Texas AandM University suggests older adults are far better at making choices that lead to long-term gain.
The study, co-authored by University of Texas at Austin psychologist Todd Maddox, found older adults, at least 60 years old, are better at strategizing their decisions than those in their late teens and early 20s, who tend to focus on instant gratification.
Findings from the study, led by Darrell Worthy, professor of psychology at Texas AandM University, will be published in Psychological Science. Collaborators on the study include University of Texas psychologists David Schnyer, Jennifer Pacheco and Marissa Gorlick.
Contradicting negative stereotypes of age and reasoning ability, the results show that the wisdom that comes with age can allow people to make better decisions under some conditions. Maddox says the study gives insight into the decision-making process, which will help researchers learn more about the effects of aging in the brain.
However, in a second experiment, the older participants outperformed the younger group in choosing options that resulted in long-term gains, such as strategically storing the most amount of oxygen in "oxygen accumulators" on an imaginary space mission in Mars. In this portion of the study, 52 older adults (ages 67-82) and 51 younger adults (ages 20-26) performed decision-making tasks in which the choices they made influenced future rewards.
As part of the experiment, the researchers created a test with two oxygen extraction systems on Mars. The rewards depended on the respondents' previous choices. The respondents had to choose from two options: the "increasing option," which increased rewards in future trials, and the "decreasing option," which decreased future rewards but offered a larger immediate reward. In each permutation of the experiment, the older participants outperformed the younger group by figuring out which option led to the most long-term cumulative rewards.
"We found that younger adults performed equivalently in the experiment, but older adults were more adept at adjusting their strategy to fit the goals of the task," Maddox says.
The researchers suggest these results provide insight into how people use their brains as they age. When making choices, younger people use the ventral striatum, a region of the brain associated with habit formation and immediate rewards. As this declines with age, the psychologists theorize that people compensate by using their prefrontal cortex, an area of the brain that controls rational and deliberate thoughts.
To test this theory, Maddox and his team of researchers are conducting a neuroimaging study to determine which parts of the brain respond to immediate gratification and long-term rewards while the participants engage in decision-making tasks. Collaborators on this study include Worthy, Jeannette Mumford, psychology research assistant at The University of Texas at Austin, and Russell Poldrack, professor of psychology and neurobiology and director of the Imaging Research Center at The University of Texas at Austin.
|
__label__1
| 0.970427
|
Glenn Rufrano, president and CEO of Cushman & Wakefield, discusses what’s driving retailer expansion plans domestically and globally. Retailers are trying to find markets where they can grow the fastest. Primarily, they are looking to emerging markets like Brazil, China and India as well as dense cities in mature markets, including New York, London and Hong Kong. To make that expansion a reality, retailers turn to global brokerage firms for assistance in understanding demographics and buying patterns as well as local laws and how leases are structured from country to country.
|
__label__1
| 0.944919
|
Nucleic Acids
The third group of macromolecules found in cells contain some of the largest molecules of the body - these are the nucleic acids. There are two major groups of nucleic acids, ribonucleic acid (RNA) and deoxyribonucleic acid (DNA). Each group is composed of long chains of building block molecules known as nucleotides. There are four different nucleotides used in the formation of nucleic acids, these are adenine, thymine (uracil instead of thymine is found in RNA), guanine and cytosine (see Figure 11). Each nucleotide contains three distinct parts: a 5-carbon sugar (ribose in RNA, deoxyribose in DNA), at least one phosphate group attached to the number 5 carbon of the sugar, and one of four different nitrogenous bases that attach to the number 1 carbon of the sugar. Nucleotides are bound together via a phosphodiester bond between the phosphate group of one nucleotide and the number 3 carbon of another. In this manner, very long chains (over 1 million nucleotides long) are formed.
The primary function of DNA is as the carrier of genetic information. DNA is found only in the nucleus of the cell and is the genetic component of the chromosomes. DNA is usually double stranded, meaning that two strands of nucleotides are attached to one another via H-bonds between different bases. Since each base can only form H-bonds with only one type of base (adenine binds with thymine, cytosine with guanine), the sequence of bases in one strand must complement the sequence of the other (and therefore, if you know the sequence in one strand, you can deduce the sequence of the other). During cell replication, the two strands separate and each is used as a template for a new strand. In this manner, one double stranded DNA molecule is perfectly replicated into two identical strands, one for each daughter cell. DNA is made only from preexisting DNA (any exceptions do not concern us in this course).
RNA is involved in synthesis of all proteins by the cell. As you should know, proteins are synthesized on cytoplasmic organelles known as ribosomes. Also, in order to make a particular protein, you need to know the sequence of amino acids. DNA contains codes for the amino acid sequence for all proteins made by the cell. However, DNA doesn't leave the nucleus and ribosomes don't enter the nucleus. So there is a problem, how does the code for a protein (that's in the DNA) get to the ribosome? The answer is through RNA.
Let us suppose that a cell needs to make a particular protein, say myoglobin. Somewhere on the DNA in the nucleus is a small stretch of nucleotides that code for the sequence of myoglobin. Through mechanisms that don't concern us yet, the nucleus activates enzymes that cause a complementaly strand RNA to be synthesized using the area of DNA containing the code for myoglobin as a template. In this manner, a strand of mRNA (for messenger RNA) is synthesized (a process known as transcription) that contains the code for the amino acid sequence of myoglobin. The mRNA then leaves the nucleus, travels to the ribosome where the code is interpreted and the protein synthesized (a process known as translation). This process occurs for the synthesis of all proteins and is summarized by the following:
There are two other functions of nucleotides that will be important to physiology. One is as a second messenger molecule which will be describe later in the semester. The other is the use of adenosine triphosphate (ATP, a nucleotide) as the energy currency of the cell. ATP can be hydrolyzed as shown in equation 8 with the release of energy. It is the energy derived from this reaction that the cell uses to drive almost every cellular function or reaction that requires energy. Any enzyme that catalyzes this reaction is known as an ATPase (there are many different ATPases in cells). New ATP is synthesized by the reverse of its hydrolysis using energy that comes from the metabolism of nutrients via glycolysis and the TCA cycle.
Return to Contents
|
__label__1
| 0.995361
|
Romney Is No Friend To The Free-Market
As those of us on the right have long known, a free-market economy, free of incessant Government intervention, is a hallmark of Conservatism in American politics. And, amid the skepticism, in regards to Romney’s sincerity on Conservative politics, and Limited Government, he recently made two statements that were very telling:
1. “My view is to allow the minimum wage to rise with the CPI (basically, a measurement of inflation), or with another index…”
Allow the minimum wage to rise? Keep up with inflation? Repair the (Federal) safety-net?
Minimum wage, while on the surface, may seem compassionate, it is actually a policy that keeps the skilled-workers working, and freezes out the less-skilled, and first-time workers. And, Inflation is caused by the incessant printing of money by The Federal Reserve, which devalues our currency, and causes all goods and services to rise in cost. Therefore, if I am not mistaken, Mitt Romney is basically suggesting that, under his Presidency, inflation, the minimum wage, and the welfare state, are here to stay, and will be tweaked, and adjusted, by the Technocratic Manipulators in his Administration!
So, while Mitt and friends, continue to print monopoly money, and prices continue to rise – some of us, who are fortunate enough to be employed, as the minimum wage increases, will be employed, and the rest of society will survive by living in the demoralizing world of food stamps and welfare?
Minimum wage, inflation, and the Federal safety-net, are all a creation of BIG GOVERNMENT; and, over the years, has been protected, and maintained, by a Federal Government that has long forsaken, and far exceeded, it’s Constitutional Limits! All three go against the very principles of a Free-Market economy; all three add up to tax increases; and, all three fly right in the face of Conservative economic policy in The United States! Mitt Romney, not only is no friend to The Free-Market, but, he is most certainly not a friend to The United States Constitution!
Romney’s remarks only confirm, and underscore, the fact that, just because one is a successful businessman, it doesn’t mean they understand how a free-market economy is suppose to function.
I, therefore, stand by my belief that, we are not in need of a successful businessman in The White House, but, rather, a person who understands The Constitution, and will work to return us to our Constitutional Foundation!
|
__label__1
| 0.63642
|
QT Prolongation: Closing in on the Target of Meaningful Data
Experts provide an update on a troublesome (and notorious) cardiac safety issue
Jun 01, 2005
A new study in Holland suggests that yet another group of antipsychotic and gastrointestinal treatments have been linked to increased risk of sudden cardiac death. In a longitudinal study by doctors from seven medical centers in the Netherlands, Thorazine (chlorpromazine), Haldol (haloperidol), and Orap (pimozide)—as well as two gastrointestinal drugs, Propulsid (cisapride) and Motilium (domperidone)—have been linked to increased risk of irregular heartbeat.
Like many medications before them, these drugs have been shown to prolong the QT interval, the few hundred milliseconds of electrical activity that control the heart's pumping action. QT prolongation has become a significant concern for pharma and FDA since the early 1990s, when Seldane (terfenadine), a popular antihistamine headed for OTC status, was derailed by data that linked it with sudden cardiac death and life-threatening ventricular tachyarrhythmias, such as Torsades de Pointes (TdP). In the years since, an increasing number of drugs—antihistamines, antipsychotics, antidepressants, and antibacterials—have been given additional warnings or pulled from the market because they increased the QT interval.
QT prolongation is not likely to go away as an issue for the pharmaceutical industry. In 2001, FDA's Janet Woodcock told the Los Angeles Times that the agency had lost patience with drugs that caused it. "We're encouraging people, if there's QT prolongation, don't develop it," she said.
It is increasingly important for pharma researchers to understand what QT prolongation is and how it affects clinical development and drug safety.
What is the QT interval?
Cardiac Cycle
The QT interval is part of the cardiac cycle as it is represented on paper with an electrocardiograph (ECG or EKG). The cardiac cycle—a single heartbeat—starts when the atria begin to fill with blood, and ends when the ventricles recover from the contraction that propels blood throughout the body.
An ECG represents the heartbeat as a series of waves that measure electrical changes in the walls of the heart—depolarization and repolarization—that accompany the blood movement. The QT interval is the time, in milliseconds, between the depolarization (Q) at the onset of ventricular contraction and the repolarization (T) that prepares for another contraction.
What is the normal QT interval?
The normal QT interval varies with the heart rate. That's why the QT interval is corrected for what it would be theoretically, at a rate of 60 beats per minute. This is known as the QTc (corrected QT interval). The normal QTc generally is accepted to be less than 440 ms, and on average is slightly longer in females. FDA concept papers have mentioned normal QTc as:
• <430 ms in males and <450 ms in females
• borderline between 430 and 450 ms for males and between 450 and 470 ms for females.
|
__label__1
| 0.676954
|
WFP donors
Many countries, institutions, organisations, companies and individuals contribute funds to WFP every year. Choose a year to see the corresponding list of donors. The list for the most recent year is not final and is liable to change as details of contributions work their way through the system.
|
__label__1
| 0.812742
|
On Friday 18 January 2008, Jonas Smedegaard wrote:
> >agreed that setting a systemwide default is sensible,
> >but if at all posible there should be no barrier for users to trying out
> > a different desktop
> students in some situations. If a class is being taught a common topic
> (rather than each individually working independently) differences in
> interface could cause too much distraction.
I can see your point, but that doesn't stop a school from using Gnome in
one class, and KDE in another, and XFCE in yet another. (or Gnome one day,
and KDE the next).
And honestly, if the class is getting bogged down because 'start program X'
or 'go to site Y', or 'copy file X to Y' is problematic (that's pretty much
all the interaction you'll have with the DE in a non-computer class).
You'll save WAY more time in the long run by ensuring your students have
some basic computer skills before you start using the computer as a routine
(a one of computer use is a different situation, but if the computer is a
routine tool used in every class there's no contest)
> An analogy would be that the students do not get to pick the math book to
> read - they all follow the same book for consistency.
as I've said in my reply to Nigel and Andreas, the desktop is more akin to
the classroom then the textbook (which would be the site/document/program
> over "freedom of choice" for the students.
I absolutely agree that you have to get the teachers on board, but I'm also
firmly convinced that this particular issue isn't usually looked at from a
from a pedagogical perspective, but from a technical support one.
(and in a school environment the pedagogical perspective should have way
more weight).
Cheers, cobaco (aka Bart Cornelis)
Attachment: signature.asc
Description: This is a digitally signed message part.
Reply to:
|
__label__1
| 0.858785
|
Academic journal article ETC.: A Review of General Semantics
Do Words Have Inherent Meaning?
Academic journal article ETC.: A Review of General Semantics
Do Words Have Inherent Meaning?
Article excerpt
IN AUGUST 2007, PARTICIPANTS on the Institute of General Semantics Forum discussed the frequently quoted statement "words don't mean, people mean," and the question of whether or not words have inherent meaning in a thread that shares its title with this article. (1)
Before proceeding, I feel that it is necessary to lay out my understanding of the subject by giving definitions of the major words in the title.
a single unit of language that has meaning and can be spoken or written The word "environment" means different things to different people. She spoke so fast 1 couldn 't understand a word (= anything she said).
what something represents or expresses Do you know the meaning of this word? The word has several meanings.
exisiting as a natural or permanent quality of something or someone The drug has certain inherent side effects. (Cambridge Dictionary of American English)
These definitions represent the collective senses by which these terms are understood by a majority of American English speakers as corroborated in standard dictionaries. (2)
In addition to these dictionary definitions, Korzybski in Science & Sanity (hereinafter S&S), provided us with his 'definition' of 'meaning' for 'words': "... words represent abstractions of different order ..." (p.21).
Combining all of these definitions, I can provide an overall definition of the word 'word' which matches my understanding:
word: a single unit of language that represents abstractions of different order and can be spoken or written.
I will discuss the usage of 'inherent' added to this definition later.
In this paper, I am restricting the use of meaning of a word to one specific level of abstraction, namely, that which is made by a reader/hearer upon encountering that word each time as part of a message of larger, more specific context. (3)
My immediate response to the question asked as the subject of the discussion was a definite 'no'.
This passage by Milton Dawes in Time-Bindings expresses well part of my views on the subject.
1. Words, by themselves, do not have meanings. (The 'meanings' of words we read in a dictionary were assigned by lexicographers. And lexicographers depend on the meanings given to these words by other humans.)
2. If I accepted that words by themselves had meanings, I would be acting elementalistically; I would be identifying; and I would be evaluating 'allistically'.
'Meaning' involves speakers/writers, their intentions; words they use to represent their intentions; my interpretation of those words; and my responses (conscious and non-conscious, verbal and non-verbal) based on my interpretation.
Words do not mean ... Humans give meanings. We are usually unaware that we do--but if we are very attentive, we can catch ourselves in the process. (p.6)
This summarized some of my thoughts about the subject, but didn't cover all of them, and so, I decided to try to lay out completely the foundations of why I. believed as I do.
During the course of the discussion, people did appear to acknowledge that, as happens in so many of our disagreements, the individual, personal, different and multi-level evaluations of several of the significant terms, especially including 'inherent' itself, formed the root of the problem. Becoming consciously aware that this was occurring emphasizes the raison d' etre of general semantics. (4)
As one example, I evaluated that some of the participants in the Forum discussion seemed to hold that meanings, once they had been formulated and placed in a dictionary, exist independently of both the formulator and any possible reader and that this constituted the inherent meaning of the words. I have seen this same attitude among many people, sometimes expressed as; "That is the meaning of the word because that is what is written in the dictionary. …
Author Advanced search
|
__label__1
| 0.975063
|
RIES - Find Algebraic Equations, Given Their Solution
Semiserious Math Tricks
Formal Hypothesis
Some fairly serious maths has been done partly with the aid of RIES. For example, it was recently asked if there is a closed form for
SIGMAk=1..inf [ -1(k+1) ζ(2k) / 2(2k-1) ] = ζ(2)/2 - ζ(4)/23 + ζ(6)/25 - ...
where ζ() is the Riemann Zeta function. The series converges quickly and ries was used to find a guess for the answer:
$ ries 0.712688574959647755609169086586 Your target value: T = 0.712688574959647756 mrob.com/ries x = sqrt(1/2) for x = T - 0.00558179 {44} x = e^-(1/3) for x = T + 0.00384274 {57} x = sqrt(5)/pi for x = T - 0.000926032 {60} [...] x = pi/(e^pi-1)-(1-pi/2) ('exact' match) {128} [...] --LHS-- --RHS-- -Total- max complexity: 67 62 129 dead-ends: 2785473 5271937 8057410 Time: 0.557 expressions: 187907 320749 508656 distinct: 95554 94028 189582 Memory: 14848KiB Total equations tested: 8984751512 (8.985e+09)
The answer is π/2 coth(π/2) - 1 = π/(e^π-1) + π/2 - 1, and can be proven reasonably easily using the series sum definition of the Zeta function, an identity (based on the calculus of residues) for the cotangent, and the simple identity coth x = i cot(ix).
Wild Guessing
Successive Refinement (Newton-Raphson Method)
To get a better approximation, add 1.442 and 0.00024957:
ries 1.44224957
(other answers not shown)
ries 1.442249570307408
(other answers not shown)
(and so on...)
Forgotten Identities
|
__label__1
| 0.641604
|
Ken Livingstone's approach to climate change was counterproductive. Johnson's green policies must resonate with ordinary people
For the first time in British politics, a mainstream candidate for high office, Ken Livingstone, put climate change at the heart of his campaign. Yet, against expectations, he lost. But while it has been said that majoring on green issues was partly the reason, I believe it was his approach to environmentalism that turned people off.
By reducing the complex environmental challenges we face to the single issue of carbon, the mayor lost sight of the broader environmental concerns of ordinary people. He understood the fundamental importance of climate change. But because he failed to link it to people's lives, there was a backlash.
The congestion charge, for instance, was undoubtedly brave, but it attracted criticism. Not even the mayor's own agency, Transport for London, claimed the charge would cause significant reductions in CO2. What began as a solution to congestion and emissions soon took on the appearance of a punishment.
If instead, the mayor had guaranteed that all of the money raised would be invested in alternatives to the car, and if he had applied the increased charge only to cars bought after its introduction, then people would probably have accepted it.
So the first advice I have for the new mayor, Boris Johnson, is that his green policies must be congruent with people's real lives. He must develop an environmentalism that actually resonates.
Congestion and rising emissions can both be tackled in ways that add to, rather than detract from, our quality of life. Take dedicated school buses, for example. Nearly a fifth of all traffic on the roads in the morning is accounted for by the school run. In North America, more than half of all children travel to school by bus. We need a similar programme in London.
The new mayor should also make use of the Thames. It is the equivalent of a six-lane highway running through the middle of London but has been scandalously underused for both freight and passengers. An improved river service could be funded by cancelling the wholly unnecessary motorway-style bridge Ken Livingstone proposed to build across the Thames at Thamesmead, saving £400m and enormous amounts of new car traffic.
We cannot significantly reduce emissions without also addressing the issue of energy – how we use it and how it is generated. A pound invested in energy efficiency buys seven times more energy solution than a pound invested in nuclear power. For example, we know that retrofitting old homes could lead to a 60% reduction in CO2 from the housing sector by 2050.
Livingstone had what he called a "major programme" for the subsidised retrofitting of homes and GLA buildings, but the domestic element of this was worth a couple of million pounds at most; not enough to do more than a fraction of homes, and the "subsidised" price charged was often higher than the usual market rate.
Johnson needs to expand both the domestic and the institutional aspects of the programme – which can be self-financing, over time, through lower energy bills – and work out how the domestic element can be leveraged.
Livingstone did useful work on the hugely important technology of decentralised energy, power generated in mini power plants close to where it is to be used, allowing the heat involved in the process to be captured and saving up to two-thirds of all electricity lost by complicated long-distance distribution networks. These kinds of systems already flourish in other parts of the world, notably the Netherlands.
London should also adopt a version of the highly successful German system of paying homeowners for energy that they return to the grid, which makes microgeneration an investment decision, not an ethical one. A single town in Bavaria with 200,000 people generates more solar power than the whole of the UK.
These are key issues. But, as ever, an environmental policy that focuses only on carbon can often deliver anti-environmental consequences. A policy, for instance, that makes it harder for people to park on our high streets often simply diverts customers to nearby supermarkets with their ever-available free parking. The effect is the erosion of the very shops that help to define our communities, and the new mayor must create a more level playing field between small traders and large operators. Either parking regimes should be relaxed for town-centre parking or, less likely, imposed for out-of-town and superstore parking.
The death of our independent retailers is a growing problem. In the past six years, London is estimated to have lost more than 7,000 of them. But is also an area where Johnson can introduce significant policy change.
For example, he has real power in strategic planning. He can impose a pan-London ban on any further large-scale shopping centre and supermarket development, since it creates enormous demands for car and HGV transport, as well as undermining the viability of traditional high streets. Sub-post offices are the cornerstones of many shopping parades, so Johnson must go through with his legal challenge to post office closures.
The mayor should also, as far as he can, impose a presumption against change of use – from pubs or small shops to residential, for instance. As a landlord and a service provider, he must end discrimination against small shops. Where developments may not fall within his "strategic" powers, the mayor should consider sponsoring local referendums to exert pressure on councils and the dreaded planning inspectorate.
Food is another issue that combines quality of life and the environment. As we know, poor diet is a factor in rising NHS expenditure and probably even in antisocial behaviour and crime. If our schools had a bias in favour of sustainable local produce, we'd see the market flooded with good quality food. We'd also see a significant reduction in the amount of fuel used to ship and fly food around the world.
However, the sad truth is that every one of these policies risks being for nothing if we continue to pursue Livingstone's crazy population growth objective. In the medium term, Livingstone envisaged a city of 8-8.5 million people. The effect of this increase will be felt in many ways, not least housing. At the moment, this pressure is increasingly being relieved by building over suburban gardens, classified by the government as mere "brownfield" land. The latest figures show we are losing the equivalent of an area twice the size of Hyde Park. The reason we've seen the immigration of hundreds of thousands of eastern Europeans is that our own people lack the skills we require. Developing London's existing human potential must be the right way forward.
London's problems should be seen in a wider context. We have allowed a disproportionate amount of economic activity to become centralised in and around London, which adds to the pressure on housing, even while other parts of the country are experiencing the emergence of ghost towns. The alternative is better transport links across the country to enable businesses to flourish throughout. Britain has less high-speed rail infrastructure than Belgium, and dramatically less than France. The new mayor needs to lobby with all his might for the construction of reliable and effective links between our cities.
Far from being marginal, the environment is the Clapham Junction of politics: a place through which many mayoral priority lines run, from housing to employment to crime. By driving forward this agenda, Boris Johnson can answer Londoners' longing for a better quality of life. London may be a much richer city than it was, but it is also a less happy one. Any mayor who changes that will truly be worthy of re-election.
This is an edited version of an article appearing in The Million Vote Mandate: The Challenges facing Boris Johnson, a report published by Policy Exchange and Localis. To read more, click here.
|
__label__1
| 0.700037
|
Who We Are
Who we are:
With the innovative and visionary project of spreading Brazilian culture to other cultures, Brazil Dance World was born in Toronto, Canada in 2005. It has offered Brazilian dance classes and performances until 2014 and organized unique events such as the Brazilian Beat: Canada Dance Congress. The Brazilian Beat was the first non-profit event in Canada that aimed to promote Brazilian dance and to unify and showcase the work of Brazilian dance professionals from Toronto and from other parts of the country. Recently, Brazil Dance World has started to work on amplifying the benefits it has promoted to its community. Innovative projects will be implemented from 2016, aiming to strength the Brazilian artistic community in Toronto.
|
__label__1
| 0.915734
|
Pork tongue asado
casaveneracion.com pork tongue asado
Pork tenderloin and rolled pork loin are commonly used in cooking “asado”. So, I wanted to be different; I used pork tongue. I did it before, but as the base for a fried rice recipe. This time, I cooked it as an entree. The basic ingredients and techniques are the same as the fried rice recipe; the variations are mainly in the amount of seasonings, spices and liquid. While very little sauce was required in preparing the “Pork Tongue Asado Fried Rice”, this dish required more liquid at the end of the cooking time since the pork tongue was supposed to be served in its own sauce.
Ingredients :
3 pcs. of pork tongue, cleaned and washed in vinegar
1 whole onion
1 whole garlic
1 tbsp. of minced garlic
1 onion, diced
1 thumb-sized piece of ginger, julienned
1 star anise
1 bay leaf
6 peppercorns
1/4 c. of dark soy sauce
1/8 c. of sugar
1 tbsp. of cornstarch
1 tbsp. of cooking oil
2 tbsp. of Hoisin sauce
salt and pepper
1/2 tsp. of sesame seed oil
Cooking procedure :
Wash the pork tongue under running water. Remove all visible fat, catilages, etc.
Place the vinegar in a glass bowl. Add the pork tongue. Using your hands, “wash” the pork tongue in the vinegar until any sliminess and unpleasant smell is gone. Another alternative is to boil the pork tongue in the vinegar with 1 c. of water. Once it boils, remove the pork tongue and discard the water and vinegar. With a knife, scrape off the outer skin of the tongue. Rinse the tongue.
Place the tongue in a clean casserole and cover with fresh water. Add the star anise, bay leaf, whole garlic, whole onion, peppercorns, soy sauce and sugar. Bring to a full boil. Remove scum as it rises. Lower heat and simmer for 1 to 1-1/2 hours or until tender when pierced with a pork. Transfer tongue to a plate and cool completely. Cool the broth as well.
Cut the tongue diagonally into 1/4-inch slices. Set aside.
Using a clean cloth (like muslin), strain the broth. You will need 1-1/2 cups. Add water if there is not enough broth left. Stir the cornstarch into the strained broth.
Heat a skillet or wok. Add the cooking oil. Saute the minced galic and diced onion. Add the sliced tongue and stir-fry over high heat until the meat starts to brown. Pour in broth-cornstarch mixture. Bring to a boil. When sauce is thick and clear, add hoisin sauce. Lower heat and simmer for about 30 seconds. Turn off heat and stir in sesame seed oil.
|
__label__1
| 0.987927
|
Astronomers have been puzzled by powerful radio-wave bursts that appear for only a few milliseconds, but emit as much energy as the sun does over the course of 300,000 years.
What could create that much energy? According to a new study published in Science, one likely candidate is a neutron star collapsing into a black hole, an event recently dubbed a blitzar.
"When the black hole forms, the magnetic field will be cut off from the star and snap like rubber bands," explains astronomer Heino Falcke in New Scientist.
Another leading theory is that the radio-wave bursts come from magnetars, which are highly magnetic neutron stars.
The waves could also be caused by two colliding neutron stars, evaporating black holes, or an entirely new type of astrophysical event, according to James Cordes, an astronomer at Cornell University.
The intense bursts were first discovered six years ago. Recently, astronomers found four of them while sweeping the sky with the Parkes radio telescope in New South Wales, Australia.
The resulting study now concludes that they are probably common occurrences, appearing as often as every 10 seconds. Despite the fact that these bursts appear all the time, only six of them have been observed.
That is because telescopes can only observe small patches of sky, meaning “you have to look for a long time before seeing many,” Dan Thornton, an astronomer at the University of Manchester, tells Discovery. “This is why we have only detected a handful so far.”
Unlike most radio waves we detect, these came from beyond our Milky Way galaxy, originating between six billion and nine billion years ago. That would make them around half as old as the universe itself.
Scientists are hoping that the radio-wave bursts can help shed light on what kind of gas fills the gaps between galaxies.
|
__label__1
| 0.835939
|
Israel has the third highest price in the world for gasoline, according to a Bloomberg survey published last week, and the situation is unlikely to improve anytime soon.
Globes reported on Thursday, that the price of self-service 95 octane gasoline, which is government-controlled, could rise from the current NIS 7.70 per liter to as much as NIS 8.25 per liter on September 1, due to the rise in the price oil and the VAT hike, which will come into effect on the same day.
Norway tops the "Bloomberg Ranking", at $10.19 per gallon in the second quarter, 4.4 percent more than in the preceding quarter. However, Norway ranks 52nd in pain at the pump, because of the country's high average daily income of $272. It is followed by Turkey, at $9.41 per gallon, but 7th in the pain at the pump ranking, because the average daily income is $30 per day.
The price per gallon of premium gasoline in third-placed Israel is $9.28, and the pain at the pump rank is 31st: "The average daily income in Israel is $87, and it takes 11% of an average day's wages to buy a gallon of gas," says Bloomberg, which did not include Israel in its previous survey.
"Gas prices have led to widespread discontent and political demonstrations over the cost of living. Prime Minister Binyamin Netanyahu has intervened to prevent prices from rising with the global price of oil, most recently when he lowered price 2.9% on June 1, according to the Energy and Water Resources Ministry."
Bloomberg added, "While the country taxes gas, it simultaneously subsidizes oil. Israel paid about $565 million in subsidies in 2010, a relatively small contribution to the world's $409 billion in global fossil-fuel subsidies."
Hong Kong and the Netherlands are in fourth and fifth place in the "Bloomberg Gas Price Ranking." Venezuela is at the bottom of the rankings, with consumers paying $0.09 per gallon of gasoline. Above it are Saudi Arabia, Kuwait, and Egypt.
|
__label__1
| 0.525856
|
Vocabulary Builder
Vocabulary Builder
Improve Your Writing
• Boost your vocabulary
• See words in the context of real sentences
• Learn by association and by definition
• Master a new lexicon!
Get Started Below
Vocabulary Word
Word: ambush
Sentences Containing 'ambush'
2012 looks to be a busy year for Ambush Entertainment.
2nd/7th Cav and the ambush near LZ Albany.
After the ambush, "Na-tio-tisha" led his band of warriors northwest through the Tonto Basin.
Although the Crusader force consisted only of 375 knights, Saladin hesitated to ambush them because of the presence of highly skilled generals.
As he reflects on his isolation from the world, he overhears Ueda and the rest of the heads of the Yoshioka plot to ambush him.
Both methods can discourage pursuit while the raid or ambush force withdraws Mining and Improvised explosive devices.
Crowe meets with Maddox to swear that he did not set him up for Dekker's ambush.
Despite seemingly being affiliated with the Godwins, however, Sialeeds incinerates a Godwin ambush of the Prince's force.
Dr. Polaris is one of the villains waiting to ambush the Freedom Fighters in a warehouse south of Metropolis in the beginning of "Infinite Crisis".
Having beaten off the ambush, the British continued their withdrawal to Bushehr.
He told Trakeena about the location of the Silver Goblet, then escaped and set up an ambush for her.
Helu had been caught off guard by Su's ambush and suffered a large amount of casualties.
HMS "Ambush" was the latest "Astute"-class boat to be commissioned.
In 1407, Theiddat, who was with a special group of Hanthawaddy forces who were waiting to ambush Minkhaung, gave a warning to his brother at a critical moment, allowing him to escape.
In fact Logan had not been one of the guards but one of the men in the ambush party.
Jade appears to test Liu Kang and attempts to seduce him, later leading the other Earthrealm warriors to an ambush.
Kenyon saved Castle's life by killing several enemy soldiers and dragging Castle to safety after he was wounded in an ambush.
Louis Ambush of the National Professional Soccer League.
Minkhaung escaped death on the warning by his brother Theiddat who was with Pegu troops to ambush him.
Rather than approach him, and knowing he was there to ambush him, Higgins simply went home.
Santana's successor, on his death in an Indonesian ambush in 1998, was by Taur Matan Ruak.
Schenck quickly assembled a party of irregulars from family members and neighbors and set an ambush for the British as they returned from their mission.
Soon after, Collins was killed at an ambush at Béal na Bláth, County Cork.
The captured soldier said the rebels' victory on the bridge was due to an ambush on government soldiers as they were busy retreating, indicating that they had lost control over Misrata.
The Confederate forces under Colonel Stand Watie attempted to ambush a Union supply convoy led by Colonel James M. Williams.
The deputies guarding the brothers ran away, in league with the ambush party.
The gun taken from Constable Clements was found by security forces after the ambush.
The Inca general commanded to fortified the mountain pass at Vilcaconga where the Spaniards would have to pass, and managed to ambush them, with great losses for the invaders.
The newly revived Kirigi attempts to ambush Stick, but he is no match for the Chaste warriors, who collectively are able to defeat him.
The surviving members of Barton's posse who managed to escape the ambush and pursuit by the gang, fled back to Los Angeles.
They were unsuccessful in attempting an ambush of a Butterfield Overland stagecoach.
This Doctor Polaris was also among the villains in the ambush of the JSA led by Tapeworm.
This feud continued, and Treacheron tricked Trakeena into searching for a silver goblet, just so that he could ambush her once he was free from his cell.
Thorn and Supergirl later ambush and capture Ivy and turns her into the police.
Unfortunately the aliens ambush the ship, and use their unique methods to trick the survivors of the "Light Brigade" into failing their mission.
More Vocab Words
::: actuary - someone who advises insurance companies
::: bicameral - two-chambered as a legislative body
::: coiffure - hairstyle
::: misapprehension - error; misunderstanding; V. misapprehend
|
__label__1
| 0.554973
|
Pavel Hlushchanka
Pavel Hlushchanka
Scala Developer
Zhodino, Belarus
What's the difference
5 years experience of web applications development, last 2 years working only with Typesafe stack and related technologies. I have rich experience in designing and developing desktop applications using AWT/Swing/JavaFX. I have a Bachelors in Software Engineering from Belarussian State University of Informatics and Radioelectronics. As remote developer i'm working more than one year. I am responsible and well-organized. I aspire continuously develop my skills, for ones of the main goals are a de…
Tests Taken
Name Percentile Score
Java Test v2
|
__label__1
| 0.575143
|
Imagine Casting
Imagine Casting
The Imaginography
Actor Imaginography
1. Animal House ... Larry 'Pinto' Kroger
2. The Batman Series ... Robin/Tim Drake
3. Buffy the Vampire Slayer II ... Alexander "Xander" Harris
4. The Catcher in the Rye ... Holden Caulfield
5. Go Ask Alice ... Joel Reems
6. Harry Potter and the Goblet of Fire ... Viktor Krum
7. The Hills Have Eyes ... Bobby Carter
8. Just Ella ... Jed
9. The Outsiders ... Sodapop Curtis
10. The Perks of Being a Wallflower ... Charlie
11. Stranger in a Strange Land ... Valentine Michael Smith
12. This Lullaby ... Chris Starr
13. The Warriors (television miniseries) ... LC (Destroyers' scout)
Site News
Popular Titles
The Nest
Eternal Sunshine of the Spotless Mind(1990s)
The Purge (2003)
Piranha 3D (2000)
If Alexandre Aja's version of Piranha 3D was made 10 years ago. Plot: After a ...
Lost password?
|
__label__1
| 0.999924
|
The most important thing to know about the causes of depression is that we don’t really know the answer to this question. It is generally believed that all mental disorders are caused by a complex interaction and combination of biological, psychological and social factors. This theory is called the bio-psycho-social model of causation and is the most generally accepted theory of the cause of disorders such as depression by professionals.
Some types of depression run in families, suggesting that a biological vulnerability can be inherited. This seems to be the case with bipolar disorder. Studies of families in which members of each generation develop bipolar disorder found that those with the illness have a somewhat different genetic makeup than those who do not get ill. However, the reverse is not true: Not everybody with the genetic makeup that causes vulnerability to bipolar disorder will have the illness. Apparently additional factors, possibly stresses at home, work, or school, are involved in its onset.
In some families, major depression also seems to occur generation after generation. However, it can also occur in people who have no family history of depression. Whether inherited or not, major depressive disorder is often associated with changes in brain structures or brain function.
People who have low self-esteem, who consistently view themselves and the world with pessimism or who are readily overwhelmed by stress, are prone to depression. Whether this represents a psychological predisposition or an early form of the illness is not clear.
In recent years, researchers have shown that physical changes in the body can be accompanied by mental changes as well. Medical illnesses such as stroke, a heart attack, cancer, Parkinson’s disease, and hormonal disorders can cause depressive illness, making the sick person apathetic and unwilling to care for his or her physical needs, thus prolonging the recovery period. Also, a serious loss, difficult relationship, financial problem, or any stressful (unwelcome or even desired) change in life patterns can trigger a depressive episode. Very often, a combination of genetic, psychological, and environmental factors is involved in the onset of a depressive disorder.
|
__label__1
| 0.612962
|
July 3, 2015
AmosWEB means Economics with a Touch of Whimsy!
Today's Index
Yesterday's Index
Skipped lunch altogether.
Bought by another.
Ate lunch at home.
Brought lunch from home.
Fast food drive through.
Fast food dine in.
All-you-can eat buffet.
Casual dining with tip.
Fancy upscale with tip.
More About the Index
Least useful compass direction?
ADVISORY COUNCILS, FEDERAL RESERVE SYSTEM: Three support committees that provide feedback to the Board of Governors of the Federal Reserve System to assist in its assorted regulatory responsibilities, including Federal Advisory Council, Thrift Institutions Advisory Council, and Consumer Advisory Council. The Federal Advisory Council is a broad ranging council comprise of commercial bankers. The Thrift Institutions Advisory Council is comprised of representatives of thrift institutions. The Consumer Advisory Council is comprised of consumer credit representatives.
Visit the GLOSS*arama
Macroeconomic problems arise when the macroeconomy does not satisfactorily achieve the goals of full employment, stability, and economic growth. Unemployment results when the goal of full employment is not achieved. Inflation exists when the economy falls short of the stability goal. These problems are caused by too little or too much demand for gross production. Unemployment results from too little demand and inflation emerges with too much demand. Stagnant growth means the economy is not adequately attaining the economic growth goal. Each of these situations is problematic because society is less well off than it would be by reaching the goals.
Unemployment arises when factors of production that are willing and able to produce goods and services are not actively engaged in production. Unemployment means the economy is not attaining the macroeconomic goal of full employment.
While attention is usually focused on the unemployment of labor, such as the time Pollyanna Pumpernickel was laid off from her job at the OmniMotors Car Company, any of the four factors of production can suffer unemployment. For example, The Wacky Willy Company might be operating one of its Stuffed Amigos factories at half capacity or Herb Haberstone might leave a section of his farmland uncultivated.
Unemployment is a problem because:
• Less output is produced and thus the economy is less able to address the scarcity problem.
• The owners of unemployed resources receive less income and thus have lower living standards.
Inflation arises when the average price level in the economy consistently and persistently increases. In other words, prices generally rise from month to month and year to year. With inflation the economy is not attaining the stability goal.
Inflation is an average increase in prices, with some prices rising more than the average, some rising less, and some even declining. As such, not every member of society is likely to experience exactly the same inflation.
Inflation is a problem because:
• The purchasing power of financial assets such as money declines, which reduces financial wealth and lowers living standards.
• Greater uncertainty surrounds long-run planning, especially the purchase of durable goods and capital goods.
• Income and wealth can be haphazardly redistributed among sectors of the economy and among resource owners.
The Business Cycle
Unemployment and inflation tend to vary with business-cycle instability. At some times, unemployment is less of a problem and inflation is more. At other times, unemployment is more of a problem and inflation is less. Consider how these two problems connect to the two primary phases of the business cycle.
• Contraction: The contraction phase of a business cycle is characterized by a general decline in economic activity. Aggregate demand is less, meaning less output is produced, and thus fewer resources are employed. For this reason, unemployment tends to be a key problem. However, because markets are more likely to have surpluses than shortages, inflation tends to be less of a problem.
• Expansion: The expansion phase of a business cycle is characterized by a general rise in economic activity. Aggregate demand is higher, production is greater, and more resources are employed. Demand for production often outpaces the ability to supply the production. Under these circumstances, because markets are more likely to have shortages than surpluses, inflation tends to be the primary problem. However, with robust production and jobs aplenty, unemployment tends to be less of a problem.
Stagnant Growth
The third problem of stagnant growth arises because the supply of aggregate production is not increasing at a desired pace or is even declining. An increase in the total production of goods and services is generally needed to keep pace with an increase in the population of society and expectations of a rising living standard. Stagnant growth exists if total production does not keep pace. This means the macroeconomic goal of economic growth is not attained.
Reasons for stagnant growth can be identified with a closer look at the quantity and quality of the resources used for production.
• Quantity: The available quantities of the four factors of production--labor, capital, land, and entrepreneurship--can restrict the growth of production.
The quantity of labor is based on both the overall population and the portion of the population willing and able to work. Should either decline, then growth is not likely to keep pace with expectations. If, for example, Edgar Millbottom decides to quit his job and spend his time doing nothing but vegetating on his parents living room sofa, then the total quantity of labor declines.
The quantity of capital depends on the amount of investment expenditures relative to the depreciation of the existing capital stock. If investment expenditures should decline or depreciation increase, then the economy is less likely to grow. If, for example, restrictive government regulations and high taxes discourage The Wacky Willy Company and similar manufacturing companies from building new factories, then the total quantity of capital declines.
• Quality: The quality of the four resources can also lead to stagnant growth. The two most noted resource quality influences are technology and education. The lack of technological progress, which could result from allocating fewer resources to scientific research can limit increases in the quantity of resources. Along a similar line of reasoning, allocating fewer resources to education can also limit resource quality.
Recommended Citation:
MACROECONOMIC PROBLEMS, AmosWEB Encyclonomic WEB*pedia,, AmosWEB LLC, 2000-2015. [Accessed: July 3, 2015].
Check Out These Related Terms...
| unemployment | inflation | macroeconomic sectors | macroeconomic markets | macroeconomic theories |
Or For A Little Background...
| macroeconomics | macroeconomic goals | full employment | business cycles | business cycle phases | stability | economic growth | factors of production |
And For Further Study...
| contraction | expansion | potential real gross domestic product | shortage | surplus | circular flow | economic growth, sources | economic growth, production possibilities | investment, production possibilities | unemployment, production possibilities | full employment, production possibilities | technology |
Search Again?
Back to the WEB*pedia
State of the ECONOMY
e-commerce sales
1st Quarter 2015
$80.3 billion
Up 3.5% from 4th Quarter 2014 US Census Bureau
More Stats
[What's This?]
Today, you are likely to spend a great deal of time flipping through the yellow pages looking to buy either a replacement remote control for your stereo system or a computer that can play video games and burn DVDs. Be on the lookout for telephone calls from former employers.
Your Complete Scope
This isn't me! What am I?
The penny is the only coin minted by the U.S. government in which the "face" on the head looks to the right. All others face left.
-- Theodore Roosevelt, 26th US president
Producer Price Index
A PEDestrian's Guide
Xtra Credit
User Feedback
| About Us | Terms of Use | Privacy Statement |
Thanks for visiting AmosWEB
Copyright ©2000-2015 AmosWEB*LLC
Send comments or questions to: WebMaster
|
__label__1
| 0.923288
|
ISLAM, Dr M Zulfiquar Ali (University of Rajshahi, Bangladesh) by bim75537
Diverse Rites of Passage of the Terrace Ethnic Communities:
A Study of Barind Tract in Northwestern Bangladesh
The paper discusses the diverse rites of passage that two terrace ethnic
communities observe in their everyday lives from birth to death. The paper
targets their life stages, from conception, birth, and childhood to elder status
and death, through their adolescence and adulthood. It also endeavors to
point toward the changes in their life cycle from the mundane to miraculous
events occurring in the interplay of their biological development and cultural
rites. The paper, primarily based on data gathered through observation, focus
group discussions, oral histories, and case studies, elucidates the cultural
diversities between the rites of passage of two ethnic communities in close
proximity and identical geographic environment. Finally, the paper adopts
cultural advocacy in making suggestions for ethnic cohesion in adapting to the
changes occurring in their subsistence that affect their rites of passage.
To top
|
__label__1
| 0.610381
|
Marubeni Corporation
Marubeni is a general trading company covering the following sectors: food materials, food products, textiles, materials, pulp and paper, chemicals, energy, metals and mineral resources, transportation machinery, power projects and infrastructure, plants and industrial machinery, finance, logistics and information industry, and real estate development and construction. It has 57 overseas branches and offices and 30 overseas corporate subsidiaries with 61 offices, for a total of 118 offices in 65 countries/areas.
|
__label__1
| 0.991735
|
• Tous les prix incluent la TVA.
En stock.
Expédié et vendu par Amazon.
Emballage cadeau disponible.
Quantité :1
Symbiosis: An Introductio... a été ajouté à votre Panier
+ EUR 2,99 (livraison)
D'occasion: Bon | Détails
Vendu par EliteDigital FR
État: D'occasion: Bon
Commentaire: Livre expédié par avion depuis New York. Veuillez s'il vous plaît tenir compte d'un délai de livraison moyen de 7 à 15 jours ouvrés. Veuillez svp également noter que ce livre peut contenir des annotations ou des passages soulignés ou montrer des traces d'usure.
Vous l'avez déjà ?
Repliez vers l'arrière Repliez vers l'avant
En savoir plus
Voir cette image
Symbiosis: An Introduction to Biological Associations (Anglais) Broché – 21 septembre 2000
Voir les 3 formats et éditions Masquer les autres formats et éditions
Prix Amazon Neuf à partir de Occasion à partir de
"Veuillez réessayer"
EUR 1,95
"Veuillez réessayer"
EUR 87,57
EUR 70,09 EUR 32,39
Offres spéciales et liens associés
Détails sur le produit
En savoir plus sur les auteurs
Dans ce livre
(En savoir plus)
Parcourir les pages échantillon
Couverture | Copyright | Table des matières | Extrait | Index
Rechercher dans ce livre:
Commentaires en ligne
Il n'y a pas encore de commentaires clients sur Amazon.fr
5 étoiles
4 étoiles
3 étoiles
2 étoiles
1 étoiles
Commentaires client les plus utiles sur Amazon.com (beta)
Amazon.com: 1 commentaire
6 internautes sur 6 ont trouvé ce commentaire utile
Little long, but very thorough overview 28 avril 2005
Par M. J. Kielecki - Publié sur Amazon.com
Format: Broché
Symbiosis by Surindar Paracer and Vernon Ahmadjian is an extensive view into the remarkable world of symbiotic relationships across all different organisms throughout the varying Kingdoms. The topics covered range from viral and bacterial pathogenesis, the symbioses possible in the origins of the Eukaryotic cell and fungal relationships between plants, animals, and fungi. Also covered are the symbiotic relationships that compose parasitic infections, animal parasitism, plant-pollinator relations, behavioral and social symbioses, and finally, co-evolution. The book does an excellent job in separating the levels of symbioses as they span through the varying bacteria, protozoa, fungi, plants, and animals. Also, brief examples of previous research are given as well as numerous references to these experiments.
The first topic discussed in Symbiosis is that of viral associations with differing organisms such as humans, insects, and fungi. An in depth approach is taking discussing the multiple taxonomic variations found in the seven main viruses. Pathogenesis such as HIV in humans is touched on as well as the replication methods that viruses use in order to infect their hosts. After the viruses, the bacteria and their effects on animals, protozoa, and other bacteria are approached. The topics approached include predatory bacteria and the parasitism of amoebas within human intestinal tracts. Bacterial bioluminescence as found within many marine species of fish and squid are explained as well. Finally, the topic of rumen microbial ecosystems is approached and a thorough explanation of the bacterial association is explained. The topic of bacterial pathogenesis touches upon the topics of Salmonella, Mycobacterium tuberculosis, and E. coli. The detail covered in the text includes both the possible origins of the varying bacteria and the molecular compositions of the varying species.
The symbiotic relationships found among plants are discussed including the Nitrogen fixing bacteria found within legumes and other plants. Other plants affected by symbiotic relationships include the Bryophytes and Cycads. Due to these organisms extended history, the extent of time that a symbiotic relationship has been shared is clear and impressive. The angiosperms are touched upon briefly dealing with such diseases as vascular wilts, soft rots, scabs, and cankers.
An interesting chapter focuses mainly solely on the Serial Endobymbiosis theory and similar symbiotic cell theories such as the Hydrogen Hypothesis. In extreme detail these topics are diagrammed and explained as how the mitochondria and chloroplasts have found there where within other cells. Also included in this endosymbiosis theory are the acquisition of microtubules for movement, peroxisomes, hydrogenosomes, and even the nucleus of cells. An interesting viewpoint is explored as the host cell being analogous to that of an intracellular ecosystem.
A book cannot be written on symbiosis without dealing with the fascinating world of fungi. In Symbiosis the fungal associations found between protozoa and animals are discussed first. The intriguing topic of predatory fungi is explored in great depth including the multitudes of trap types that fungi used. The world of insects and their relations with fungi is touched upon as well discussing the wood wasp and scolytid beetle. The fungal gardens maintained by some of these creatures for nourishment as well as some wasps and ants are of extreme interest. The chapter immediately following tackles fungal associations found in fungi, algae, and especially plants. The topic of lichens is explained, exampled, and discussed in great depth including types of lichens, distribution, dispersal and reproduction, as well as the recognizing mechanisms between fungi and algae/cyanobacterium, case pending. After lichens are thoroughly discussed the topic of mycorrhiza is approached and discussed in great depth including vesicular and arbiscular forms as well as ectendomycorrhiza and ericoid mycorrhiza, dealing with coniferophyta and heather families, respectively. Some topics of fungal associations with plants are approached and interesting methods such as castration of the plant and devastating rust, smut, and mildew diseases.
The next world explored encompasses protozoa and there mutualistic and parasitic relationships on plants, animals, and other protozoa. The topic of ruminant symbioses is revisited with ciliates as well as that found within the tadpoles of amphibian genus Opalina. A fascinating occurrence found in both Opalina and other organisms is the ability for the parasite to correspond with the life cycle of the organism. The largest portion of the chapter deals with malaria and the mechanisms involved in the complex transfer and history of the disease. This chapter supplies excellent diagrams and life-cycle charts to plot the life cycles and mechanisms used by the protozoa and the insects or animals they inhabit. The marine world is briefly approached in the relationships among sea sponges and anemones as well as jellyfish. Some of these marine species have changed their behavior drastically in order to maximize the photosynthesis of their endosymbiotic partners such as the Cassiopeia xamachana or upside down jellyfish. Many cases are given of the photosynthesis adaptations in the marine and intertidal world of these creatures.
The stomach churning chapter of animal parasitism is certainly one to make you second guess your future food choices. This chapter deals specifically with flukes, nematodes, tapeworms, and parasitoids and goes into great depths of the organisms, their methods, and the eventual unfortunate outcomes of their hosts. As with previous chapters the extensive diagrams allow the reader to properly understand the conveyed paths used by the worms in their travels through intermediate host and into their desired system. The fascinating topic of parasitoids is approached and the insect-worm relationships are viewed in some depth including the famous fig and wasp situations of mutualism and co-evolution.
Dealing with the angiosperms the topic is brief, but concise. This chapter is an excellent lead into the final chapter of co-evolution as it deals with tree-ant symbioses as well as the extremely co-evolved world of plants and pollinators, and the sycamore fig-gall wasp association is touched in greater deal. The final portion of the chapter deals with parasitic plants such as the dodders, mistletoes, and the world's largest flowering plant, the Rafflesia arnoldii.
Possibly the best topic of the book was saved for last dealing with behavioral and social symbiosis and co-evolution. The topic of cleaning fish is dealt with in great deal as well as the modifications that can be found in host-parasite interactions. Social parasitism found in wasps, ants, and termites is discussed as well as that of cowbirds and their highly developed brood parasitism shared with cuckoos. The book ends with an overview of the molecular and genetic approaches to viewing symbiosis. Although it gets somewhat dense at this point it is important to understand the relationships found between genetic polymorphism and its common occurrence among individuals who share symbiotic relationships.
On the whole, Symbiosis does an excellent job of covering the dense world of symbiotic relationships in a relatively short amount of space while still giving multiple examples, detailed drawings, and uncountable references for further investigation. This book is a definite read for any novice interested in the world of symbiotic relationships or any well developed biologist interested in learning more through brief examples and extensive references.
|
__label__1
| 0.983524
|
Genetic disorders by liaoqinmei
Genetic disorders
Know all the mutations listed and some examples
a. Point mutations- a single nucleotide base is substituted for another (aka missense)
SCA is an example of missense/point mutation
b. Non-sense mutation occurs when and amino acid codon is changed to terminator
Beta thalessemia is an example of a non-sense mutation
c. Trinucleotide repeat mutations- amplification of sequence of 3 nucleotides (250-4000 repeats)
Nucleotide repeat mutations- Fragile X syndrome
d. Frame-shift mutation occurs when 1 or 2 base pairs are added or deleted altering the reading
Cystic fibrosis is a frame-shift mutation example
“CATCH 22” problem
a. 22q11 deletion syndrome
b. C- congenital heart defects
c. A- Abnormal facies (dysmorphia)
d. T- Thymic hypoplasia (T- cell defects)
e. C- Cleft palate
f. H- Hypocalcemia
g. Connected with DiGeorge syndrome
Diseases caused by mutations in receptor/transport proteins
Familial hypercholesterolemia
Very common (1 in 500 adults)
FH is due to a mutation in the LDL receptor on the cell surface
Heterozygotes and homozygotes and their different presentations
Heterozygotes Homozygotes
LDL receptor Present but low Absent
Cholesterol High Very high
Symptoms Cholesterol on tendon sheathes, Xanthomas in childhood, MI
athersclerosis, CAD early (die 15-20 y/o)
Diseases caused by mutations in enzyme proteins
1. Know that PKU, Galactosemia, Lysosomal storage disease and Glycogen storage disease are all due to
mutations in enzyme proteins
2. PKU-
Lack phenylalnanine hydroxylase (PAH) so they can’t make tyrosine
Mental retardation, pale skin/hair (little melanin)
Early diagnosis is essential for avoidance of dietary phenyalanine to prevent mental retardation
3. Galactosemia-
Lack to galactos-1-phosphate uridyltransferase (galactose glucose)
Children will have hepatomegaly, spelnomegaly, juaundice, hypoglycemia, mental retardation and
4. Lysosomal storage diseases
Tay- Sach’s- Hexoaminidase A
a. death by age 2
Gaucher’s – Glucocerebrosidase
a. Type 1- adult onset
b. Type 2- infant onset, deadly
Niemann- Pick- Sphingomyelinase
a. death by age 5
Also know the presence of cherry red spots in the retina causing blindness is seen in Tay- Sach’s
and Niemann- Pick disease
Glycogenoses (Glycogen storage disorders)
Von Gierke’s- Glucose-6-phosphatase glycogen builds up in the liver causing hepatomegaly
and liver failure
Mc Ardles- muscle phosphorylase- causing cramps after exercise
Pompe’s- Glucosidase- cardiomegaly and eventual cardiac failure by age 2
Diseases caused by mutations in proteins that regulate cell growth
Neurofibromatosis types 1 and 2
Both are autosomal dominant
NF1- aka von Recklinghausen’s disease
Lesions include:
a. Pedunculated nodules
b. Multiple neurofibromas
c. Pigmented skin lesions (Cafe au lait spots)
d. Pigemented iris harmartomas (Lisch nodules)
e. Most serious complications is transformation into a tumor called a Neurofibrosarcoma
f. Due to chromosome 17 defect
NF2- aka acoustic neurofibromatosis
a. Chromosome 22 deficiency
b. Bilateral acoustic neuromas
c. Neurofibromas
d. Cafe au lait spots
Disease Protein defect
Marfan syndrome Fibrillin
Osteogenesis imperfecti Collagen
Ehlers-Danlos syndrome Collagen
Familial hypercholesterolemia LDL receptor
Cystic fibrosis Transmembrane protien regulator
Tay Sachs disease Hexoaminidase
Phenylkeotonuria Phenylalanine hydroxylase
Galactosemia G1P uridyltransferase
Neruofibromatosis type 1 Neurofibromin
Down’s syndrome
Autosomal disorder and the most common chromosomal disorder
Trisomy 21
The most common cause is meiotic nondisjunction. Some scenarios:
a. 95% of cases 47XX+21/47XY+21
b. 4% (Roberstonian translocation) t(14;21)
c. 1-2% (mosaics) 46XX/47XX+21
i. mosaics show much milder symptoms
Sex chromosome disorders
Kleinfelter’s-
a. Male hypogonadism
b. Most are 47XXY
c. 15% are some form of mosaic (46XY/47XXY)
d. Clinical signs include: small testes, infertility, mild retardation
Turner’s syndrome-
a. Female hypogonadism
b. 55% are missing on X chromosome
c. The remaining 45% are mosaics (46XX/45XO)
d. Clinical signs include: Poor development of female secondary sex characteristics, broad chest,
webbed neck , widely spaced nipples, primary amenorrhea due to rudimentary ovaries
Single gene disorders with atypical patterns of inheritance
Fragile X syndrome
a. abnormality of the X chromosome
i. defect localized to Xq27.3 (this is the fragile portion that breaks off)
b. Clinical features: large mandible, severe retardation, long face, enlarged testicles, This is the
second most common cause of mental retardation
c. Due to multiple tandem triplet repeat mutation via a mutation in the FMR-1 gene
Prader-Willi and Angelman syndromes
a. PW- mental retardation- with obesity, small hands and feet
b. AW- mental retardation- with inappropriate laughter (happy puppets)
Leber Hereditary Optic neuropathy- know the symptoms and cause
a. Caused by a mutation of mitochondrial genes carried in the mother
b. Expression is variable due to the maternal problems
c. Causes degenerative neuropathy with progressive bilateral los of central vision and blindness
Genetic screening tests
a. Early detection of effected individuals - ie maternal alpha-feto screening for Down’s syndrome
and newborn screening for PKU
Alpha feto protein key in detection of DS and neural tube defects
b. Carrier detection
i. Key in Tay-Sach’s disease (in Ashkenazi Jews), use the Hex A test (for hexoaminidase A)
because it can help decrease problems associated with the disease by 95%
ii. Test mothers for AFP, HCG and unconjugated estriol for Down’s syndrome
iii. Also done in Thalessemias and SCA
Principles in treatment of genetic disease
a. The three R’s
i. Restriction
ii. Replacement
iii. Removal
b. Restriction- used in PKU (remove dietary phenylalanine), G6PDH deficiency (restrict drugs and
antimalarials), Familial Hypercholesterolemia (remove dietary choelsterol)
c. Replacement- Used in hemophilia A (give pts factor A), Alpha-1-antitrypsin deficiency (give pts
alpha-1-antitrypsin, liver transplant in familial hypercholesterolemia, SCA/ADA deficiency (add
bone marrow)
d. Removal- In Wilson’s disease (remove excess copper), in familial polyposis (remove the colon
with polyps in it)
Disorders of the Immune system
HLA classes involved in disease
a. Ankylosing spondylitis- HLA-B27
b. Diabetes mellitus- HLA- DR3/DR4
Hypersensitivity diseases
a. Type I hypersensitivity
1. Examples-
a. Skin diseases- urticaria, eczema, acute dermatitis and angioneurotic edema,
b. Anaphylactic shock- ex. penicillin shock, seafood allergy, etc
2. Basic pathophysiology- IgE activation and degranulation of the mast cells
Remember normally IgE is protective against parasitic infections
b. Type II Hypersensitivity
a. Know all the subtypes
Complement mediated cytotoxicity
a. Cause: In this system complement is activated causing cell lysis
Hemolytic disease of the newborn (Erythroblastosis fetalis)
Goodpasture’s syndrome- Abs against basment membrane of the lung and
kidneys causing pneumonitis and glomerulonephritis
Autoimmune hemolytic anemia (transfusion reaction)
ADCC (Antibody-dependent cell-mediated cytotoxicity)
a. Cause: Lysis of Ab coated target cells by killer cells breaking Fc receptors
which engage the Fc portion of IgG
b. Transplant rejection
c. Tumor immunity
Antibody-mediated cellular dysfunction
a. Cause: Abs deregulate cell function withou producing cell injury
b. Grave’s disease- Abs bind TSH receptors causing hyperthyroidism
c. Myesthenia gravis- Abs bind ACh receptors blocking neuromuscular
d. Hyperthyroidism
e. Pernicous anemia
c. Type III hypersensitivity (immune complex-mediated)
a. Immune complex deposition is the problem, both local and systemically
b. Local- Arthus reaction- this is a reaction at the site of antigen injection showing necrosis
with necrotizing vasculitis
c. Systemic- Serum sickness, poststreptoccocal glomerulonephritis, SLE, Rheumatiod
arthritis, polyarteritis nodosa, polymyositis
All cause acute inflammation, fibrinoid necrosis (damage of vessels leading to
d. ALL OF THESE ARE GLOMERULAR PROBLEMS because immune complexes get
deposited in the glomerulus
e. These do not cause pyelonephritis
d. Type IV hypersensitivity (cell-mediated)
a. aka Delayed type hypersensitivity
b. The main problems is CD4 T-cell secreting cytokine
c. Examples- TB
d. Know the tests associtaed with TB
Mantoux reaction- erythema and induration following injection of tuberculin is an
indication of past TB, or BCG vaccination
Granulomatous inflammations
Transplant rejection
a. Allographs can cause and immune response (rejection) by types II, II, IV hypersenstivities
HLA-DR is the most important factor in rejection
b. Hyperacute rejections – leads to ischemic infarction of the graft in hyperacute rejection mainly
due to preformed anti-donor antibodies. Can cause fibrinoid necrosis in very severe cases
c. Acute rejection- includes type II,II, and IV hypersensitvities (humoral and cellular rections).
Most commonly presents with renal failure
Humoral rejection- due to deposition of Abs. This will cause necrotizing arteritis
Cellular rejection- Extensinve interstitial mononuclear infiltration. This can cause focal
tubular necrosis of kidneys
d. Chronic rejection- slow with progressive renal failure, no acute changes
e. GVH disease- know it happens when immunologically competent cells are transplanted into
immunologically crippled recipients. CTL will damage recipient’s tissues
Problems like this occur mostly in the liver, skin and gut mucosa
Jaundice, skin rashes, diarrhea occur
CTLs are T-cell infiltrating the organs in GVH disease
Autoimmune diseases
a. SLE- systemic lupus erythematosus
Lots of other diseases will look like this thus all similar diseases are called collagen vascular
Other collagen vascular diseases include: Rheumatoid arthritis, systemic sclerosis,
Criteria for SLE: remember a few major ones: ANA antibodies, renal disease, butterfly rash
Not all autoimmune diseases are collagen vascular consider: Hashimoto’s thyroiditis, Grave’s
disease, Myasthenia gravis, Ulcerative colitis (all are non-collagen vascular
HLA-DR2/3 are important with connection to SLE
Damage to tissue occurs via type II and III hypersensitivity
a. Fibrinoid necrosis of small arteries
Death most commonly due to kidney disease- glomerular diseases such as
glomerulonephritis due to Ab deposition on the glomerular basement membrane
Associated conditions: Libman-Sack’s endocarditis, and other nephritis’
Occurs mostly in females 1:10 ratio
ANA Ab’s are detected in virtually all patients, the most specific test for SLE is anti-double
stranded DNA
Immunodeficiency diseases
Read thru them all
Primary immunodeficiency
a. Bruton’s disease- problem of agammaglobulinemia
X-linked trait
Absence of B-cells leads to recurrent bacterial infections
b. Swiss-type/ combined immunodeficiency- both B and T lymphocytes are gone
Caused by an ADA deficiency
Young death (~2 y/o)
c. Thymic hypoplasia- lack of T-cells (aka DiGeorge’s syndrome)
22q11 deletion syndrome closely related to DiGeorge’s
Failure of the thymus to develop
Disabled CMI: viral, fungal and mycobacterial disease
d. Most common primary immunodeficiency disease is isolated IgA deficiency
Pulmonary and GIT infections common
1:700 develop this
Secondary immunodeficiency
a. AIDS is 4th leading cause of death between 15 and 54
3 methods of transmission: sexual, parenteral and mother to child
Window period- 3-7 weeks for Abs to develop
Test for HIV is ELISA- will not detect all HIV-2 infections
Attacks immune and nervous system
a. Attacks CD4 T-cells by binding with GP120
b. Normal CD4:CD8 ratio is 2:1, but it will drop to 1:1 in AIDS
c. >200 CD4/mL then diagnose full blown AIDS
d. Read the box on page 12 and know the phases of AIDS
Stage Signs/Symptoms
Early acute Decreased CD4 cells, viremia, and widespread seeding of lymphoid tissues
Seroconversion occurs after the window period
Non-specific symptoms (sorethroat, diarrhea, etc) which resolve in 3-6
Middle chronic Group II-Asymptomatic
Group III- Possible general lymphadenopathy and low level HIV replication,
may last 7-10 years
Final crisis phase Pneumonia, Diarrhea, multiple opportunistic infections, Kaposi’s sarcoma,
AIDS dementia, lymphomas common
This is a disease in which amyloid, a pathologic proteinaceous substance is deposited
extracellularly in a variety of tissues and organs producing pressure atrophy
Some immune system problems underlie this disease
b. Most common amyloidosis in the US- multiple myeloma causing primary amyloidosis and
expressing the protein AL (amyloid light chains)
Multiple myeloma will excrete Ig in the urine or light chains known as Bence-Jones proteins (causing
c. ATTR- A prealbumin that is associated with Senile cardiac amyloidosis and hereditary
d. B2 microglobulin- seen in patients with chronic renal failure getting dialysis. This cannot be
removed and gets accumulated giving rise to carpal tunnel syndrome
e. Secondary amyloidosis- seen in chronic infections such as TB, osteomylitis, and rheumatoid
f. Organs effected by amyloidosis
Kidney- most common site of damage and death
a. amyloid in the glomeruli casues destruction
Spleen- 2 patterns of deposition
a. Small nodular deposits in spelnic follicles called Sago Spleen
b. Large map like areas of deposits in the splenic pulp called Laraceous spleen
Heart- becomes enlarged due to amyloid deposition leading to pressure atrophy
(cardiomyopathy and CHF).
Amyloidosis seen Disease caused by Proteins seen
Primary amyloidosis Multiple myeloma AL
Secondary amyloidosis Chronic inflammation AA
Hereditary/Senile cardiac Familial amyloid ATTR
amyloidosis polyneuropathies
Hemodyalisis associated Chronic renal failure B2-microglobulins
13. Infectious diseases
a. Chlamydial infection
Causes urethritis and cervicitis (also prostatitis in males)
Most frequent STD disease in the US with 3 million new cases (second to Gonorrhea)
Mostly caused by C. trachomatis
Newborns infected with it can also get inclusion conjunctivitis
b. Keratoconjunctivitis due to chlamydial infections
One of the leading causes of blindness
Causes scarring and ulceration of the conjunctiva
c. Lymphogranulmoa venereum (LGV)-
STD
Not common
Lesions at the penis, vagina, cervix
Occurs in 3 stages
1. Small ulcer at site of infection
2. Granulomatous lymphadenitis (buboes) and pus discharge
3. Elephantiaisis, esthiomene
d. Rickettsial diseases
Typhus is a louse borne disease caused by Rickettsia prowazekii
a. a typhus nodule is a small vessel lesion of the brain and other organs showing focal leukocytic
infiltration and microglial proliferatoin
Rocky mountain spotted fever is a tick borne infection
1.Rocky mountain spotted fever (ricketsia ricketsii)
a. Hallmark is the eschar (a rash)
b. Meningitis may occur
e. Mycoplasma-
These are tiny organisms also called PPLOs or Eaton agents
M. pneumonia accounts for 10-30% of all primary interstitial pneumonias
Produces cold agglutinins
Common in military recruits and institutions (prisons)
Bacterial infections
remember gram positive and gram negative can both cause severe septicemia and shock
Gram positive can cause Toxic shock syndrome (vaginal tampons)
Streptococcal infections
Have 2 patterns of disease: spreading of suppurative infections, and poststrep. hypersensitivity
(causing glomerulonephritis, rheumatic fever, and erythema nodosum)
d. Menigococal infections
Severe septicemia
Death
DIC and hemorrhages in the adrenals causing a severe shock called Waterhouse-Friderichsen
e. Gonococcal infections
Causes sterility in males and females.
PID leading to sterility (due to tubo-ovarian abscesses) in females and ectopic pregnancy
Causes destruction of the epididimis in males causing sterility
Can cause right upper quadrant pain around the liver called Fitz-Hugh-Curtis-Syndrome
f. Gram negative rods cause:
Endotoxic shock- a hypotensive shock due to bacterial endotoxins
Nosocomial infections
Remeber Legionella infections
a. Caused by L. pneumophilia
b. Causes DIC, shock, renal failure and most commonly respiratory failure
c. Pontaic fever- a mild form, usually self limiting
g. Legionella infections
These are commonly respiratory infections caused by L. penumophilia and others
The bugs are found in cooling systems
2 disease presentations
a. Pontaic fever- mild, self-limited febrile disease
b. Legionnaire’s disease- severe pneumonia with a 15-20% fatality rate
Legionnaire’s presents with dry cough, slow pulse, chest and abdominal pain. Eventually
respiratory failure, shock, DIC and renal failure can occur
May present as lobular pneumonia or confluent bronchopneumonia
Infectious diarrheas
a.Typhoid fever
Typhoid carriers are asymptomatic humans, they can develop the disease if they become
compromised. Remember humans are the only reservoir
It causes, toxic coagulation of the cardiac muscle,
Neutropenia occurs due to bone marrow suppression
Rose spots develop on the chest
b. Lyme disease
Tick borne infection (Borrelia burgdorferi)
It is a spirochete
a. Other spirochete infections include: Relapsing fever, syphilis, and Weil’s disease
3 stages
1. ECM- erythema chronicum migrans
2. Chorea, myocarditis
3. Chronic debilitating arthritis
Sexually transmitted diseases
a. Syphilis
Stage Symptoms Complications/resolution
Primary syphilis Chancre- painless, eroded and indurated Heals in 3-12 weeks
occur on penis, labia or cervic
Painless lymphadenopathy
Secondary syphilis 1-3 months post chancre
Well or with malaise
Skin rashes which are bilateral,
May show retinitis, meningitis
Tertiary syphilis Cardiovascular- aortic aneurysm, aortic Gummatous necrosis of the liver,
incompetance and narrowing of the bones and testes.
coronary ostia
Neurosyphilis- tabes dorsalis and GPI
(general paresis)
Gummas
b. Congenital syphilis
Contracted via the placenta
Causes late abortion, stillbirth
c. Tuberculosis
Caused by Mycobacterium tuberculosis
a. transmitted by inhalation, ingestion or skin inocculation
Identified by Ziehl-Neelsen Stain
Causes infective granulomas called tubercles (w/Langhans giant cells)
Primary infection is mediated by a type IV cell-mediated hypersensitivity reaction, this plays a major
role in caseating tissue destruction (large cavities in the lung)
What is primary TB
a. Granulomas called Ghon foci and enlarged hilar lymph nodes, together called Ghon complex are
found subpleurally
What is secondary TB
a. Seen in people who have been previously infected, via a recativation
b. Coin lesions with hemoptysis
Some possible outcomes of TB
a. May induce amyloidosis
b. If the tubercle bacilli gain access to the blood they can form yellow-white lesions in distant organs
such as the eye, bone marrow, spleen and liver. This is called miliary TB
To top
|
__label__1
| 0.931434
|
Public Release: Multiple sclerosis: Damaged myelin not the trigger
University of Zurich
Millions of adults suffer from the incurable disease multiple sclerosis (MS). It is relatively certain that MS is an autoimmune disease in which the body's own defense cells attack the myelin in the brain and spinal cord. Myelin enwraps the nerve cells and is important for their function of transmitting stimuli as electrical signals. There are numerous unconfirmed hypotheses on the development of MS, one of which has now been refuted by the neuroimmunologists in their current research: The death of oligodendrocytes, as the cells that produce the myelin sheath are called, does not trigger MS.
Neurodegenerative hypothesis obsolete
With their research, the scientists disprove the so-called "neurodegenerative hypothesis", which was based on observations that certain patients exhibited characteristic myelin damage without a discernable immune attack. In the popular hypothesis, the scientists assume that MS-triggering myelin damage occurs without the involvement of the immune system. In this scenario, the immune response against myelin would be the result - and not the cause - of this pathogenic process.
Focus on immune system
|
__label__1
| 0.994547
|
The Nazis’ Chocolate Bomb
The term “Death by Chocolate” usually refers to a dessert recipe — chocolate cake served with chocolate ice cream, chocolate syrup, sometimes with chocolate brownies or chocolate candies or chocolate shavings on top. Chocolate, chocolate, and more chocolate. For most, Death by Chocolate seems like a wonderful idea. The Nazis agreed — but took the term more literally.
The likely target of the chocolate? Gizmodo states that the Nazis envisioned the British Royal family falling prey to the ruse, opening up a bar of chocolate only to find a very rude — and deadly — surprise. According to the BBC, while explosives camouflaged as food were found on Nazi agents in Turkey, none made it to the UK. However, four similarly constructed cans of peas, en route to Buckingham Palace, did make it to Ireland before being intercepted.
Of course, it’s incredibly unclear as to why the Nazis believed that a member of the Royal family would be opening up their own cans of peas.
Bonus fact: Say or hear a word over and over again, and it may lose its meaning to you. Almost all of us have experienced it, and you may have experienced this after reading the first sentence of the first paragraph above. (Your brain, after a while, may have been unable to center in on the meaning of the word “chocolate.”) This happens due to “a psychological phenomenon in which repetition causes a word or phrase to temporarily lose meaning for the listener, who can only process the speech as repeated meaningless sounds,” as explained by Wikipedia. The name of that phenomenon is “semantic satiation.”
From the ArchivesWhen the Nazis Invaded America: Another Nazi saboteur plan that went awry.
RelatedA fake chocolate bar that is actually a calculator.
|
__label__1
| 0.620765
|
In nature, the shape of a gemstone is determined by its natural crystal structure and the conditions under which the crystal developed. To enhance the natural beauty of the crystal and to provide a safe shape for mounting, gem cutters form natural gemstones into precise shapes. These shapes typically include a number of flat, symmetrical planes, called facets, which reflect light to add sparkle and brilliance to the finished stone.
Gemstone cutting is based in science. Each gem material has a known refractive index which allows a gem cutter to determine how light rays will bend as they pass through the stone. Using this information a gemstone can then be precisely shaped to best enhance its natural beauty.
If a well shaped multi-faceted stone is viewed from above it will appear very bright across the entire surface. This brightness results from light rays being reflected directly from the top surface, as well being reflected within the gemstone and back to your eye. You cannot see through a well cut gemstone, even though the natural material is translucent, since almost all of the light is being reflected back to the viewer. [Obviously this is not the case with stones which are intentionally shaped with larger facets, such as a traditional emerald cut.]
If a gemstone is not as well shaped it will be possible to look down on the top surface and see through to the point at the bottom of the stone. This transparent effect is called a "window." Windows detract from the brilliance and color of a stone, since light be allowed to pass directly through the materials without reflecting back to the viewers eye.
Not all gemstones are faceted. For example, opals are suited to a smooth, rounded surface, and are often found with pleasing shapes which naturally highlight their internal flashes and sparkles. Other gems are formed into smooth, rounded shapes called cabochons. Some "cabo's" are also referred to as "star" gems due to the distinctive light pattern which appears as a result of inclusions in the stone.
Understanding cuts in Gemstones :-
When grading and appraising gemstones, cut may not be as influential as the other C's like color, clarity, and carat weight, but it is definitely an influencing factor when it comes to the gemstones overall beauty. To properly evaluate the cut of a given gemstone, you must not only study the face-up view or the surface or top view but study it from all other angles as well. An excellent cut can reduce loss on carat weight but enhance its looks to breathtaking proportions at the same time.
Common Cuts Used on Gemstones :
1. Brilliant Cuts :
A brilliant-cut gemstone usually has three flat polished surfaces per facet. They are positioned in such a way to radiate the best light from the gemstone. Gemstone cutters also make sure that the angles will enhance the brilliance of the gemstone. Brilliant cuts are mostly used for diamonds and transparent gemstones.
Some facets will have one or more shapes like stars, hearts, kites, and lozenges. Variations of the brilliant cut include the naivet or boat-shaped marquise, pear-shaped pendeloque, and oval shape. Oval shapes are suitable for gemstones with lower carat weight because they can make them appear bigger.
The most popular variation of all is the full-cut round brilliant. It has fifty-eight facets, presently the greatest count for brilliant cut gemstones. The single brilliant cut, on the other hand, has seventeen to eighteen facets. For gemstones used in earrings and pendants, the briolette variation is mostly used to provide it with circular cross-section teardrop shapes. Brilliant cuts with triangular dimensions are called trilliants while square brilliant cuts are also known as princess cuts.
2. Step Cuts :
Another popular cut for a gemstone is the step or trap cut. Step cuts are best used for colored gemstones because they possess four-sided table facets and girdles as well as parallel quadrilateral facets. The term step cut was used because this gemstone cut bears similarities with a staircase. Step cuts have fewer facets than brilliant cuts.
One well-known variation of a step cut is the baguette. It is rectangular in shape but with square corners. Emerald cuts are also quite popular. Its name was derived from its consistent use with emeralds. Emerald cuts remove the corners and form an octagonal shape. Clipping off the corners protect delicate gemstones like emeralds and facilitate setting of gemstones at the same time. Other popular variations for step cuts are window, table, radiant, and oval.
The best advantage of step cuts is its ability to enhance a gemstones color, making the color richer and appearing to have originated straight from the belly of the gemstone.
3. Mixed Cuts :
Mixed cuts for gemstones are mostly combinations of brilliant and step cuts. The crown or top portion of a gemstone will resemble a brilliant cut while the pavilion or bottom portion of a gemstone will receive a step cut. At times, the two cuts will appear side by side. Mixed cuts are also characterized by their rounded outlines. Many transparent gemstones like rubies and sapphires are often cut this way. Gemstones with mixed cuts are also commonly set in prongs.
Variations for mixed cuts include but are not limited to cushion, zircut, pear or teardrop, and oval.
4. Cabochon Cuts :
A gemstone with a cabochon cut will appear rounded on top and flat on the bottom. At times, gemstones will only appear in this cut. Height of a gemstones dome with a cabochon cut varies. The name is derived from the French term used for bald heads. Cabochon cuts are simplest to make, and that is why you will often see them used on affordable gemstones and those that will not benefit from faceting.
5. Fancy Cuts :
Any other cut besides those mentioned above is usually referred to as fancy. A checkerboard cut, for instance, will have a combination of a large table facet on top and a mixed cut. A rose cut will have a round girdle outline, flat base, dome-shaped crown, and facets of a brilliant cut.
When judging the cut of a gemstone, start by evaluating it face up. See if the gemstone shows uniform color distribution and radiates light in the best possible way. Gemstones cut with large windows are unappealing. Lastly, recheck all other angles and determine if the cut took both carat weight and looks into consideration.
|
__label__1
| 0.94102
|
Working Paper No. 10-03
Drill Baby Drill?
Karen Maguire
October 2010
This paper examines the role of federal elected political influence and market factors in determining the acres of oil and natural gas leases issued on Bureau of Management (BLM) lands in the western United States between 1978 and 2008. This paper seeks to determine if a political party and ideology of the federal political environment influence the number of acres that are leased and if there is disparate federal political influence in states that have a large amount of federal lands. Using a random effects Tobit model for a 17-state sample of the westernmost states in the contiguous United States, the findings indicate that more conservative Congressional and Presidential influence lead to additional leasing. The results are consistent across Senate committee leaders, Senate majority leadership, and the President’s office. The influence of politics on leasing is not found to be stronger in states with more federal lands,however.
|
__label__1
| 0.997485
|
GEZLONG transparent
Gezlong is the pioneer online travel platform in Turkey. It is a members-only site where travelers can find exclusive discounts for top tier hotels and tours from different parts of the world for a limited time. All the hotels and tours featured at Gezlong are seen and approved by world acknowledged travel editors.
|
__label__1
| 0.9939
|
Ellis Island MMO
Ellis Island is a Massively Multiplayer Online Game set in New York City that provides players with the experience of immigrating to the United States during the 1920s. The core focus of Ellis is the emergent progression of characters throughout play. A player’s character has a certain set of traits based on the nationality and background they choose at the beginning of the game. As the player progresses through Ellis Island and completes various quests and events of his or her choosing, the traits and qualities of the character change to reflect the outcomes of these endeavors. Players also choose an aspiration, which is a professional goal that they desire to reach. However, depending on the choices a player makes, he or she might wind up in a completely different line of work.
Several other systems in Ellis Island are designed to emphasize the immigrant experience:
• Language - Players must gain proficiency in and communicate through various languages
• Contacts - Players must make contacts, including characters (NPCs) and other players
• Reputation - Players gain or lose reputation with their contacts, which affects how those contacts treat them
• Social Conflict - A card game symbolizing an argument between two people. Players use Logic, Passion, Ethics, and Deception to build their argument while simultaneously picking apart their opponents’.
More Information Can Be Found At: EllisIslandGame.com
|
__label__1
| 0.684752
|
CSG Midwest
CSG Midwest
CSG Midwest
How can states better ensure that soon-to-be high school graduates are leaving their K–12 education systems ready to succeed in college or the workforce? For states, finding answers to that policy question has never been more important because of a continuing economic trend—jobs are demanding more and more skills and increasingly requiring some level of postsecondary training.
State officials and policymakers have been focused on college- and career-readiness for several years yet challenges still exist to graduate students with the skills and competencies necessary to obtain sustainable employment. 2015 promises to be another busy year concentrated on implementing best practices and enacting innovative policies that prepare America's youngest students for entry into school, create environments for all students including those at-risk, and offer a variety of experiences so students participate in work-based opportunities. In order to ensure a world-class education for all students, leaders will likely address these top 5 issues facing states this year.
On Thursday, Nov. 20 a group of state legislators and education officials met with staff from the White House Intergovernmental Affairs and representatives from the U.S. Departments of Education and Health and Human Services. An update on the Administration's priorities, the Workforce Innovation and Opportunity Act (WIOA) and critical early education initiatives were discussed.
|
__label__1
| 0.991896
|
Encyclopedia of Ancient Egypt
The illustrated Encyclopedia of Ancient Egypt covers time period from the 3150 BC to 30 BC. Easily access the maps, timeline, information about the dynasties, pharaohs, laws, culture, government, military and more.
Fully illustrated with maps, art, and photographs.
Always have the guide available for a quick reference.
Tags: egyptian civilization , ancient egyptian drawings of people , ancient egyptian civilization , egypt civilization , photograph of ancient egypt laws , encyclopedia of ancient egypt , map of ancient egyptian civilization , ancient egypt encyclopedia , map of ancient egypt in a encyclopedia
Users review
from 3 reviews
|
__label__1
| 0.837357
|
LATEST: An Australian publication has issued an apology after it revealed British royal Prince Harry had been fighting on the army front line in Afghanistan. The 23-year-old, who is third in line to the throne, was deployed to the war-torn country late last year (07) but the British government issued a media blackout on the situation to avoid any potential kidnap plots involving the young royal. However, Australia's New Idea magazine insists when it ran the story in January (08) it was unaware of an agreement between the British Ministry of Defence and major news organisations not to disclose the prince's deployment, in order to protect him and his fellow soldiers. The royal was pulled out of the country following the report last month (Feb08). The magazine said in a statement, "We do acknowledge that our actions in publishing the story can be reasonably viewed as insensitive and irresponsible."
|
__label__1
| 0.864044
|
For example, Harry Styles takes a photo of him of his mom from when he was a toddler and advances it the present. The other people in the photos age along with the boy band member but don’t interact with them at all, until the end. Liam Payne’s photo is him in formal wear with his family; Zayn Malik and his sister have their moment in his choice, while Niall Horan shares a musical moment with his brother.
The track is the second single from One Direction's new album, "Midnight Memories," out Nov. 25.
|
__label__1
| 0.996412
|
UNISDR and China launch new urban resilience award
The award, which will be presented at a ceremony in Beijing, China on 12-14 December during the Second Mayors' Summit on Disaster Risk Reduction, comes at a time when cities across the world are facing more extreme weather events and feeling the pressure of rapid urbanization and population growth.
"The Resilient Cities Award aims to raise awareness of the importance of good planning in the face of urbanization and climate change, and advance the exchange of ideas, innovation, and investment in disaster risk reduction," said Helena Molin Valdes, Chief of the United Nations' Making Cities Resilient Campaign.
Dr. Dong Yanzhang, Executive Chairman of the WCSDA, added: "Beijing is an apt stage for this award given the huge urban expansion happening throughout China."
China is now home to the world's largest mega-cities, with more than 20 million people already inhabiting the nation's capital city of Beijing. Most of the emerging mega-cities are expanding into once rural and pastoral areas, creating further stress to eco-systems and raising concerns about future access to core resources such as clean water, food and housing.
About the Award
The Resilient Cities Award recognizes excellence in the adoption and implementation of the Ten Essentials for Making Cities Resilient, a 10-point checklist designed to help local governments assess their risks and initiate plans to improve their cities' resilience.
Applicants will be considered based on successful urban resilience efforts demonstrated through effective land-use planning, design, development, and infrastructure activities and investments that serve to reduce disaster risk.
Further consideration will also be given to efforts to raise awareness of disaster risk through successful organization and coordination between multiple stakeholders and the mobilization of funding and other resources, as well as the implementation of educational programs and training, and efforts to protect ecosystems and natural buffers to mitigate floods, storm surges and other natural hazards.
The Award Winner will receive complimentary travel and accommodation to Beijing, VIP access to the Summit and tour of the capital, a Resilient Cities 2012 Plaque, and global recognition as an international exemplar in urban resilience. The winner will also be invited to serve as a global ambassador on disaster risk reduction, engaging with multiple audiences and other city leaders at future forums and events.
Entries for the award are now being accepted and should be submitted to [email protected]. The entry deadline is 30 October 2012.
Where We Work
|
__label__1
| 0.896856
|
Search tips
Search criteria
Results 1-25 (27)
Clipboard (0)
Select a Filter Below
more »
Year of Publication
author:("reec, James M")
1. Increasing gene discovery and coverage using RNA-seq of globin RNA reduced porcine blood samples
BMC Genomics 2014;15(1):954.
Transcriptome analysis of porcine whole blood has several applications, which include deciphering genetic mechanisms for host responses to viral infection and vaccination. The abundance of alpha- and beta-globin transcripts in blood, however, impedes the ability to cost-effectively detect transcripts of low abundance. Although protocols exist for reduction of globin transcripts from human and mouse/rat blood, preliminary work demonstrated these are not useful for porcine blood Globin Reduction (GR). Our objectives were to develop a porcine specific GR protocol and to evaluate the GR effects on gene discovery and sequence read coverage in RNA-sequencing (RNA-seq) experiments.
A GR protocol for porcine blood samples was developed using RNase H with antisense oligonucleotides specifically targeting porcine hemoglobin alpha (HBA) and beta (HBB) mRNAs. Whole blood samples (n = 12) collected in Tempus tubes were used for evaluating the efficacy and effects of GR on RNA-seq. The HBA and HBB mRNA transcripts comprised an average of 46.1% of the mapped reads in pre-GR samples, but those reads reduced to an average of 8.9% in post-GR samples. Differential gene expression analysis showed that the expression level of 11,046 genes were increased, whereas 34 genes, excluding HBA and HBB, showed decreased expression after GR (FDR <0.05). An additional 815 genes were detected only in post-GR samples.
Our porcine specific GR primers and protocol minimize the number of reads of globin transcripts in whole blood samples and provides increased coverage as well as accuracy and reproducibility of transcriptome analysis. Increased detection of low abundance mRNAs will ensure that studies relying on transcriptome analyses do not miss information that may be vital to the success of the study.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-954) contains supplementary material, which is available to authorized users.
PMCID: PMC4230834 PMID: 25374277
Pig; Blood; Globin reduction; RNA-seq; Transcriptome
2. Identification of genomic regions associated with feed efficiency in Nelore cattle
BMC Genetics 2014;15(1):100.
Feed efficiency is jointly determined by productivity and feed requirements, both of which are economically relevant traits in beef cattle production systems. The objective of this study was to identify genes/QTLs associated with components of feed efficiency in Nelore cattle using Illumina BovineHD BeadChip (770 k SNP) genotypes from 593 Nelore steers. The traits analyzed included: average daily gain (ADG), dry matter intake (DMI), feed-conversion ratio (FCR), feed efficiency (FE), residual feed intake (RFI), maintenance efficiency (ME), efficiency of gain (EG), partial efficiency of growth (PEG) and relative growth rate (RGR). The Bayes B analysis was completed with Gensel software parameterized to fit fewer markers than animals. Genomic windows containing all the SNP loci in each 1 Mb that accounted for more than 1.0% of genetic variance were considered as QTL region. Candidate genes within windows that explained more than 1% of genetic variance were selected by putative function based on DAVID and Gene Ontology.
Thirty-six QTL (1-Mb SNP window) were identified on chromosomes 1, 2, 3, 5, 6, 7, 8, 9, 10, 12, 14, 15, 16, 18, 19, 20, 21, 22, 24, 25 and 26 (UMD 3.1). The amount of genetic variance explained by individual QTL windows for feed efficiency traits ranged from 0.5% to 9.07%. Some of these QTL minimally overlapped with previously reported feed efficiency QTL for Bos taurus. The QTL regions described in this study harbor genes with biological functions related to metabolic processes, lipid and protein metabolism, generation of energy and growth. Among the positional candidate genes selected for feed efficiency are: HRH4, ALDH7A1, APOA2, LIN7C, CXADR, ADAM12 and MAP7.
Some genomic regions and some positional candidate genes reported in this study have not been previously reported for feed efficiency traits in Bos indicus. Comparison with published results indicates that different QTLs and genes may be involved in the control of feed efficiency traits in this Nelore cattle population, as compared to Bos taurus cattle.
Electronic supplementary material
The online version of this article (doi:10.1186/s12863-014-0100-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4198703 PMID: 25257854
Bos indicus; Candidate gene; Residual feed intake; Single nucleotide polymorphisms
Nucleic Acids Research 2012;41(Database issue):D871-D879.
The Animal QTL database (QTLdb; is designed to house all publicly available QTL and single-nucleotide polymorphism/gene association data on livestock animal species. An earlier version was published in the Nucleic Acids Research Database issue in 2007. Since then, we have continued our efforts to develop new and improved database tools to allow more data types, parameters and functions. Our efforts have transformed the Animal QTLdb into a tool that actively serves the research community as a quality data repository and more importantly, a provider of easily accessible tools and functions to disseminate QTL and gene association information. The QTLdb has been heavily used by the livestock genomics community since its first public release in 2004. To date, there are 5920 cattle, 3442 chicken, 7451 pigs, 753 sheep and 88 rainbow trout data points in the database, and at least 290 publications that cite use of the database. The rapid advancement in genomic studies of cattle, chicken, pigs, sheep and other livestock animals has presented us with challenges, as well as opportunities for the QTLdb to meet the evolving needs of the research community. Here, we report our progress over the recent years and highlight new functions and services available to the general public.
PMCID: PMC3531174 PMID: 23180796
4. Worldwide Patterns of Ancestry, Divergence, and Admixture in Domesticated Cattle
PLoS Genetics 2014;10(3):e1004254.
The domestication and development of cattle has considerably impacted human societies, but the histories of cattle breeds and populations have been poorly understood especially for African, Asian, and American breeds. Using genotypes from 43,043 autosomal single nucleotide polymorphism markers scored in 1,543 animals, we evaluate the population structure of 134 domesticated bovid breeds. Regardless of the analytical method or sample subset, the three major groups of Asian indicine, Eurasian taurine, and African taurine were consistently observed. Patterns of geographic dispersal resulting from co-migration with humans and exportation are recognizable in phylogenetic networks. All analytical methods reveal patterns of hybridization which occurred after divergence. Using 19 breeds, we map the cline of indicine introgression into Africa. We infer that African taurine possess a large portion of wild African auroch ancestry, causing their divergence from Eurasian taurine. We detect exportation patterns in Asia and identify a cline of Eurasian taurine/indicine hybridization in Asia. We also identify the influence of species other than Bos taurus taurus and B. t. indicus in the formation of Asian breeds. We detect the pronounced influence of Shorthorn cattle in the formation of European breeds. Iberian and Italian cattle possess introgression from African taurine. American Criollo cattle originate from Iberia, and not directly from Africa with African ancestry inherited via Iberian ancestors. Indicine introgression into American cattle occurred in the Americas, and not Europe. We argue that cattle migration, movement and trading followed by admixture have been important forces in shaping modern bovine genomic variation.
Author Summary
The DNA of domesticated plants and animals contains information about how species were domesticated, exported, and bred by early farmers. Modern breeds were developed by lengthy and complex processes; however, our use of 134 breeds and new analytical models enabled us to reveal some of the processes that created modern cattle diversity. In Asia, Africa, North and South America, humpless (Bos t. taurus or taurine) and humped (Bos t. indicus or indicine) cattle were crossbred to produce hybrids adapted to the environment and local production systems. The history of Asian cattle involves the domestication and admixture of several species whereas African taurines arose through the introduction of domesticated Fertile Crescent taurines and their hybridization with wild African aurochs. African taurine genetic background is commonly observed among European Mediterranean breeds. The absence of indicine introgression within most European taurine breeds, but presence within three Italian breeds is consistent with at least two separate migration waves of cattle to Europe, one from the Middle East which captured taurines in which indicine introgression had already occurred and the second from western Africa into Spain with no indicine introgression. This second group seems to have radiated from Spain into the Mediterranean resulting in a cline of African taurine introgression into European taurines.
PMCID: PMC3967955 PMID: 24675901
5. Genome-wide association study for intramuscular fat deposition and composition in Nellore cattle
BMC Genetics 2014;15:39.
Meat from Bos taurus and Bos indicus breeds are an important source of nutrients for humans and intramuscular fat (IMF) influences its flavor, nutritional value and impacts human health. Human consumption of fat that contains high levels of monounsaturated fatty acids (MUFA) can reduce the concentration of undesirable cholesterol (LDL) in circulating blood. Different feeding practices and genetic variation within and between breeds influences the amount of IMF and fatty acid (FA) composition in meat. However, it is difficult and costly to determine fatty acid composition, which has precluded beef cattle breeding programs from selecting for a healthier fatty acid profile. In this study, we employed a high-density single nucleotide polymorphism (SNP) chip to genotype 386 Nellore steers, a Bos indicus breed and, a Bayesian approach to identify genomic regions and putative candidate genes that could be involved with deposition and composition of IMF.
Twenty-three genomic regions (1-Mb SNP windows) associated with IMF deposition and FA composition that each explain ≥ 1% of the genetic variance were identified on chromosomes 2, 3, 6, 7, 8, 9, 10, 11, 12, 17, 26 and 27. Many of these regions were not previously detected in other breeds. The genes present in these regions were identified and some can help explain the genetic basis of deposition and composition of fat in cattle.
The genomic regions and genes identified contribute to a better understanding of the genetic control of fatty acid deposition and can lead to DNA-based selection strategies to improve meat quality for human consumption.
PMCID: PMC4230646 PMID: 24666668
Fatty acid; GWAS; Bos indicus; Beef; Positional candidate gene
6. Genome-wide association and genomic prediction for host response to porcine reproductive and respiratory syndrome virus infection
Host genetics has been shown to play a role in porcine reproductive and respiratory syndrome (PRRS), which is the most economically important disease in the swine industry. A region on Sus scrofa chromosome (SSC) 4 has been previously reported to have a strong association with serum viremia and weight gain in pigs experimentally infected with the PRRS virus (PRRSV). The objective here was to identify haplotypes associated with the favorable phenotype, investigate additional genomic regions associated with host response to PRRSV, and to determine the predictive ability of genomic estimated breeding values (GEBV) based on the SSC4 region and based on the rest of the genome. Phenotypic data and 60 K SNP genotypes from eight trials of ~200 pigs from different commercial crosses were used to address these objectives.
Across the eight trials, heritability estimates were 0.44 and 0.29 for viral load (VL, area under the curve of log-transformed serum viremia from 0 to 21 days post infection) and weight gain to 42 days post infection (WG), respectively. Genomic regions associated with VL were identified on chromosomes 4, X, and 1. Genomic regions associated with WG were identified on chromosomes 4, 5, and 7. Apart from the SSC4 region, the regions associated with these two traits each explained less than 3% of the genetic variance. Due to the strong linkage disequilibrium in the SSC4 region, only 19 unique haplotypes were identified across all populations, of which four were associated with the favorable phenotype. Through cross-validation, accuracies of EBV based on the SSC4 region were high (0.55), while the rest of the genome had little predictive ability across populations (0.09).
Traits associated with response to PRRSV infection in growing pigs are largely controlled by genomic regions with relatively small effects, with the exception of SSC4. Accuracies of EBV based on the SSC4 region were high compared to the rest of the genome. These results show that selection for the SSC4 region could potentially reduce the effects of PRRS in growing pigs, ultimately reducing the economic impact of this disease.
PMCID: PMC3974599 PMID: 24592976
7. Body composition and gene expression QTL mapping in mice reveals imprinting and interaction effects
BMC Genetics 2013;14:103.
Shifts in body composition, such as accumulation of body fat, can be a symptom of many chronic human diseases; hence, efforts have been made to investigate the genetic mechanisms that underlie body composition. For example, a few quantitative trait loci (QTL) have been discovered using genome-wide association studies, which will eventually lead to the discovery of causal mutations that are associated with tissue traits. Although some body composition QTL have been identified in mice, limited research has been focused on the imprinting and interaction effects that are involved in these traits. Previously, we found that Myostatin genotype, reciprocal cross, and sex interacted with numerous chromosomal regions to affect growth traits.
Here, we report on the identification of muscle, adipose, and morphometric phenotypic QTL (pQTL), translation and transcription QTL (tQTL) and expression QTL (eQTL) by applying a QTL model with additive, dominance, imprinting, and interaction effects. Using an F2 population of 1000 mice derived from the Myostatin-null C57BL/6 and M16i mouse lines, six imprinted pQTL were discovered on chromosomes 6, 9, 10, 11, and 18. We also identified two IGF1 and two Atp2a2 eQTL, which could be important trans-regulatory elements. pQTL, tQTL and eQTL that interacted with Myostatin, reciprocal cross, and sex were detected as well. Combining with the additive and dominance effect, these variants accounted for a large amount of phenotypic variation in this study.
Our study indicates that both imprinting and interaction effects are important components of the genetic model of body composition traits. Furthermore, the integration of eQTL and traditional QTL mapping may help to explain more phenotypic variation than either alone, thereby uncovering more molecular details of how tissue traits are regulated.
PMCID: PMC4233306 PMID: 24165562
eQTL mapping; QTL mapping; Body composition; Myostatin; Imprinting; Interaction; Mouse
8. Genome-wide association and prediction of direct genomic breeding values for composition of fatty acids in Angus beef cattlea
BMC Genomics 2013;14:730.
As consumers continue to request food products that have health advantages, it will be important for the livestock industry to supply a product that meet these demands. One such nutrient is fatty acids, which have been implicated as playing a role in cardiovascular disease. Therefore, the objective of this study was to determine the extent to which molecular markers could account for variation in fatty acid composition of skeletal muscle and identify genomic regions that harbor genetic variation.
Subsets of markers on the Illumina 54K bovine SNPchip were able to account for up to 57% of the variance observed in fatty acid composition. In addition, these markers could be used to calculate a direct genomic breeding values (DGV) for a given fatty acids with an accuracy (measured as simple correlations between DGV and phenotype) ranging from -0.06 to 0.57. Furthermore, 57 1-Mb regions were identified that were associated with at least one fatty acid with a posterior probability of inclusion greater than 0.90. 1-Mb regions on BTA19, BTA26 and BTA29, which harbored fatty acid synthase, Sterol-CoA desaturase and thyroid hormone responsive candidate genes, respectively, explained a high percentage of genetic variance in more than one fatty acid. It was also observed that the correlation between DGV for different fatty acids at a given 1-Mb window ranged from almost 1 to -1.
Further investigations are needed to identify the causal variants harbored within the identified 1-Mb windows. For the first time, Angus breeders have a tool whereby they could select for altered fatty acid composition. Furthermore, these reported results could improve our understanding of the biology of fatty acid metabolism and deposition.
PMCID: PMC3819509 PMID: 24156620
Intramuscular fat; Genome architecture; Angus
9. The Vertebrate Trait Ontology: a controlled vocabulary for the annotation of trait data across species
PMCID: PMC3851175 PMID: 23937709
Quantitative trait loci; Gene association; Trait ontology
10. Structural and functional annotation of the porcine immunome
BMC Genomics 2013;14:332.
PMCID: PMC3658956 PMID: 23676093
Immune response; Porcine; Genome annotation; Co-expression network; Phylogenetic analysis; Accelerated evolution
11. Pig immune response to general stimulus and to porcine reproductive and respiratory syndrome virus infection: a meta-analysis approach
BMC Genomics 2013;14:220.
The availability of gene expression data that corresponds to pig immune response challenges provides compelling material for the understanding of the host immune system. Meta-analysis offers the opportunity to confirm and expand our knowledge by combining and studying at one time a vast set of independent studies creating large datasets with increased statistical power. In this study, we performed two meta-analyses of porcine transcriptomic data: i) scrutinized the global immune response to different challenges, and ii) determined the specific response to Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) infection. To gain an in-depth knowledge of the pig response to PRRSV infection, we used an original approach comparing and eliminating the common genes from both meta-analyses in order to identify genes and pathways specifically involved in the PRRSV immune response. The software Pointillist was used to cope with the highly disparate data, circumventing the biases generated by the specific responses linked to single studies. Next, we used the Ingenuity Pathways Analysis (IPA) software to survey the canonical pathways, biological functions and transcription factors found to be significantly involved in the pig immune response. We used 779 chips corresponding to 29 datasets for the pig global immune response and 279 chips obtained from 6 datasets for the pig response to PRRSV infection, respectively.
The pig global immune response analysis showed interconnected canonical pathways involved in the regulation of translation and mitochondrial energy metabolism. Biological functions revealed in this meta-analysis were centred around translation regulation, which included protein synthesis, RNA-post transcriptional gene expression and cellular growth and proliferation. Furthermore, the oxidative phosphorylation and mitochondria dysfunctions, associated with stress signalling, were highly regulated. Transcription factors such as MYCN, MYC and NFE2L2 were found in this analysis to be potentially involved in the regulation of the immune response.
The host specific response to PRRSV infection engendered the activation of well-defined canonical pathways in response to pathogen challenge such as TREM1, toll-like receptor and hyper-cytokinemia/ hyper-chemokinemia signalling. Furthermore, this analysis brought forth the central role of the crosstalk between innate and adaptive immune response and the regulation of anti-inflammatory response. The most significant transcription factor potentially involved in this analysis was HMGB1, which is required for the innate recognition of viral nucleic acids. Other transcription factors like interferon regulatory factors IRF1, IRF3, IRF5 and IRF8 were also involved in the pig specific response to PRRSV infection.
This work reveals key genes, canonical pathways and biological functions involved in the pig global immune response to diverse challenges, including PRRSV infection. The powerful statistical approach led us to consolidate previous findings as well as to gain new insights into the pig immune response either to common stimuli or specifically to PRRSV infection.
PMCID: PMC3623894 PMID: 23552196
Meta-analysis; Microarrays; Pig immune response; PRRSV infection
12. Genome-wide association study of infectious bovine keratoconjunctivitis in Angus cattle
BMC Genetics 2013;14:23.
Infectious Bovine Keratoconjunctivitis (IBK) in beef cattle, commonly known as pinkeye, is a bacterial disease caused by Moraxellabovis. IBK is characterized by excessive tearing and ulceration of the cornea. Perforation of the cornea may also occur in severe cases. IBK is considered the most important ocular disease in cattle production, due to the decreased growth performance of infected individuals and its subsequent economic effects. IBK is an economically important, lowly heritable categorical disease trait. Mass selection of unaffected animals has not been successful at reducing disease incidence. Genome-wide studies can determine chromosomal regions associated with IBK susceptibility. The objective of the study was to detect single-nucleotide polymorphism (SNP) markers in linkage disequilibrium (LD) with genetic variants associated with IBK in American Angus cattle.
The proportion of phenotypic variance explained by markers was 0.06 in the whole genome analysis of IBK incidence classified as two, three or nine categories. Whole-genome analysis using any categorisation of (two, three or nine) IBK scores showed that locations on chromosomes 2, 12, 13 and 21 were associated with IBK disease. The genomic locations on chromosomes 13 and 21 overlap with QTLs associated with Bovine spongiform encephalopathy, clinical mastitis or somatic cell count.
Results of these genome-wide analyses indicated that if the underlying genetic factors confer not only IBK susceptibility but also IBK severity, treating IBK phenotypes as a two-categorical trait can cause information loss in the genome-wide analysis. These results help our overall understanding of the genetics of IBK and have the potential to provide information for future use in breeding schemes.
PMCID: PMC3673868 PMID: 23530766
Keratoconjunctivitis; Pinkeye; BayesB; Threshold model; Genome-wide analysis
13. Analyses of pig genomes provide insight into porcine demography and evolution
Groenen, Martien A. M. | Archibald, Alan L. | Uenishi, Hirohide | Tuggle, Christopher K. | Takeuchi, Yasuhiro | Rothschild, Max F. | Rogel-Gaillard, Claire | Park, Chankyu | Milan, Denis | Megens, Hendrik-Jan | Li, Shengting | Larkin, Denis M. | Kim, Heebal | Frantz, Laurent A. F. | Caccamo, Mario | Ahn, Hyeonju | Aken, Bronwen L. | Anselmo, Anna | Anthon, Christian | Auvil, Loretta | Badaoui, Bouabid | Beattie, Craig W. | Bendixen, Christian | Berman, Daniel | Blecha, Frank | Blomberg, Jonas | Bolund, Lars | Bosse, Mirte | Botti, Sara | Bujie, Zhan | Bystrom, Megan | Capitanu, Boris | Silva, Denise Carvalho | Chardon, Patrick | Chen, Celine | Cheng, Ryan | Choi, Sang-Haeng | Chow, William | Clark, Richard C. | Clee, Christopher | Crooijmans, Richard P. M. A. | Dawson, Harry D. | Dehais, Patrice | De Sapio, Fioravante | Dibbits, Bert | Drou, Nizar | Du, Zhi-Qiang | Eversole, Kellye | Fadista, João | Fairley, Susan | Faraut, Thomas | Faulkner, Geoffrey J. | Fowler, Katie E. | Fredholm, Merete | Fritz, Eric | Gilbert, James G. R. | Giuffra, Elisabetta | Gorodkin, Jan | Griffin, Darren K. | Harrow, Jennifer L. | Hayward, Alexander | Howe, Kerstin | Hu, Zhi-Liang | Humphray, Sean J. | Hunt, Toby | Hornshøj, Henrik | Jeon, Jin-Tae | Jern, Patric | Jones, Matthew | Jurka, Jerzy | Kanamori, Hiroyuki | Kapetanovic, Ronan | Kim, Jaebum | Kim, Jae-Hwan | Kim, Kyu-Won | Kim, Tae-Hun | Larson, Greger | Lee, Kyooyeol | Lee, Kyung-Tai | Leggett, Richard | Lewin, Harris A. | Li, Yingrui | Liu, Wansheng | Loveland, Jane E. | Lu, Yao | Lunney, Joan K. | Ma, Jian | Madsen, Ole | Mann, Katherine | Matthews, Lucy | McLaren, Stuart | Morozumi, Takeya | Murtaugh, Michael P. | Narayan, Jitendra | Nguyen, Dinh Truong | Ni, Peixiang | Oh, Song-Jung | Onteru, Suneel | Panitz, Frank | Park, Eung-Woo | Park, Hong-Seog | Pascal, Geraldine | Paudel, Yogesh | Perez-Enciso, Miguel | Ramirez-Gonzalez, Ricardo | Reecy, James M. | Zas, Sandra Rodriguez | Rohrer, Gary A. | Rund, Lauretta | Sang, Yongming | Schachtschneider, Kyle | Schraiber, Joshua G. | Schwartz, John | Scobie, Linda | Scott, Carol | Searle, Stephen | Servin, Bertrand | Southey, Bruce R. | Sperber, Goran | Stadler, Peter | Sweedler, Jonathan V. | Tafer, Hakim | Thomsen, Bo | Wali, Rashmi | Wang, Jian | Wang, Jun | White, Simon | Xu, Xun | Yerle, Martine | Zhang, Guojie | Zhang, Jianguo | Zhang, Jie | Zhao, Shuhong | Rogers, Jane | Churcher, Carol | Schook, Lawrence B.
Nature 2012;491(7424):393-398.
For 10,000 years pigs and humans have shared a close and complex relationship. From domestication to modern breeding practices, humans have shaped the genomes of domestic pigs. Here we present the assembly and analysis of the genome sequence of a female domestic Duroc pig (Sus scrofa) and a comparison with the genomes of wild and domestic pigs from Europe and Asia. Wild pigs emerged in South East Asia and subsequently spread across Eurasia. Our results reveal a deep phylogenetic split between European and Asian wild boars ~1 million years ago, and a selective sweep analysis indicates selection on genes involved in RNA processing and regulation. Genes associated with immune response and olfaction exhibit fast evolution. Pigs have the largest repertoire of functional olfactory receptor genes, reflecting the importance of smell in this scavenging animal. The pig genome sequence provides an important resource for further improvements of this important livestock species, and our identification of many putative disease-causing variants extends the potential of the pig as a biomedical model.
PMCID: PMC3566564 PMID: 23151582
14. AnimalQTLdb: a livestock QTL database tool set for positional QTL information mining and beyond
Nucleic Acids Research 2006;35(Database issue):D604-D609.
The Animal Quantitative Trait Loci (QTL) database (AnimalQTLdb) is designed to house all publicly available QTL data on livestock animal species from which researchers can easily locate and compare QTL within species. The database tools are also added to link the QTL data to other types of genomic information, such as radiation hybrid (RH) maps, finger printed contig (FPC) physical maps, linkage maps and comparative maps to the human genome, etc. Currently, this database contains data on 1287 pig, 630 cattle and 657 chicken QTL, which are dynamically linked to respective RH, FPC and human comparative maps. We plan to apply the tool to other animal species, and add more structural genome information for alignment, in an attempt to aid comparative structural genome studies ().
PMCID: PMC1781224 PMID: 17135205
15. Prediction of Altered 3′- UTR miRNA-Binding Sites from RNA-Seq Data: The Swine Leukocyte Antigen Complex (SLA) as a Model Region
PLoS ONE 2012;7(11):e48607.
The SLA (swine leukocyte antigen, MHC: SLA) genes are the most important determinants of immune, infectious disease and vaccine response in pigs; several genetic associations with immunity and swine production traits have been reported. However, most of the current knowledge on SLA is limited to gene coding regions. MicroRNAs (miRNAs) are small molecules that post-transcriptionally regulate the expression of a large number of protein-coding genes in metazoans, and are suggested to play important roles in fine-tuning immune mechanisms and disease responses. Polymorphisms in either miRNAs or their gene targets may have a significant impact on gene expression by abolishing, weakening or creating miRNA target sites, possibly leading to phenotypic variation. We explored the impact of variants in the 3′-UTR miRNA target sites of genes within the whole SLA region. The combined predictions by TargetScan, PACMIT and TargetSpy, based on different biological parameters, empowered the identification of miRNA target sites and the discovery of polymorphic miRNA target sites (poly-miRTSs). Predictions for three SLA genes characterized by a different range of sequence variation provided proof of principle for the analysis of poly-miRTSs from a total of 144 M RNA-Seq reads collected from different porcine tissues. Twenty-four novel SNPs were predicted to affect miRNA-binding sites in 19 genes of the SLA region. Seven of these genes (SLA-1, SLA-6, SLA-DQA, SLA-DQB1, SLA-DOA, SLA-DOB and TAP1) are linked to antigen processing and presentation functions, which is reminiscent of associations with disease traits reported for altered miRNA binding to MHC genes in humans. An inverse correlation in expression levels was demonstrated between miRNAs and co-expressed SLA targets by exploiting a published dataset (RNA-Seq and small RNA-Seq) of three porcine tissues. Our results support the resource value of RNA-Seq collections to identify SNPs that may lead to altered miRNA regulation patterns.
PMCID: PMC3490867 PMID: 23139801
The newly available pig genome sequence has provided new information to fine map quantitative trait loci (QTL) in order to eventually identify causal variants. With targeted genomic sequencing efforts, we were able to obtain high quality BAC sequences that cover a region on pig chromosome 17 where a number of meat quality QTL have been previously discovered. Sequences from 70 BAC clones were assembled to form an 8-Mbp contig. Subsequently, we successfully mapped five previously identified QTL, three for meat color and two for lactate related traits, to the contig. With an additional 25 genetic markers that were identified by sequence comparison, we were able to carry out further linkage disequilibrium analysis to narrow down the genomic locations of these QTL, which allowed identification of the chromosomal regions that likely contain the causative variants. This research has provided one practical approach to combine genetic and molecular information for QTL mining.
PMCID: PMC3268380 PMID: 22303339
meat quality QTL; pig chromosome 17; integrated analysis
17. Whole genome analysis of infectious bovine keratoconjunctivitis in Angus cattle using Bayesian threshold models
BMC Proceedings 2011;5(Suppl 4):S22.
Infectious bovine keratoconjunctivitis (IBK), also known as pinkeye, is characterized by damage to the cornea and is an economically important, lowly heritable, categorical disease trait in beef cattle. Scores of eye damage were collected at weaning on 858 Angus cattle. SNP genotypes for each animal were obtained from BovineSNP50 Infinium-beadchips. Simultaneous associations of all SNP with IBK phenotype were determined using Bayes-C that treats SNP effects as random with equal variance for an assumed fraction (π=0.999) of SNP having no effect on IBK scores. Bayes-C threshold models were used to estimate SNP effects by classifying IBK into two, three or nine ordered categories. Magnitudes of genetic variances estimated in localized regions across the genome indicated that SNP within the most informative regions accounted for much of the genetic variance of IBK and pointed out some degree of association to IBK. There are many candidate genes in these regions which could include a gene or group of genes associated with bacterial disease in cattle.
PMCID: PMC3108217 PMID: 21645302
18. Probing genetic control of swine responses to PRRSV infection: current progress of the PRRS host genetics consortium
BMC Proceedings 2011;5(Suppl 4):S30.
Understanding the role of host genetics in resistance to porcine reproductive and respiratory syndrome virus (PRRSV) infection, and the effects of PRRS on pig health and related growth, are goals of the PRRS Host Genetics Consortium (PHGC).
The project uses a nursery pig model to assess pig resistance/susceptibility to primary PRRSV infection. To date, 6 groups of 200 crossbred pigs from high health farms were donated by commercial sources. After acclimation, the pigs were infected with PRRSV in a biosecure facility and followed for 42 days post infection (dpi). Blood samples were collected at 0, 4, 7, 10, 14, 21, 28, 35 and 42 dpi for serum and whole blood RNA gene expression analyses; weekly weights were recorded for growth traits. All data have been entered into the PHGC relational database. Genomic DNAs from all PHGC1-6 pigs were prepared and genotyped with the Porcine SNP60 SNPchip.
Results have affirmed that all challenged pigs become PRRSV infected with peak viremia being observed between 4-21 dpi. Multivariate statistical analyses of viral load and weight data have identified PHGC pigs in different virus/weight categories. Sera are now being compared for factors involved in recovery from infection, including speed of response and levels of immune cytokines. Genome-wide association studies (GWAS) are underway to identify genes and chromosomal locations that identify PRRS resistant/susceptible pigs and pigs able to maintain growth while infected with PRRSV.
Overall, the PHGC project will enable researchers to discover and verify important genotypes and phenotypes that predict resistance/susceptibility to PRRSV infection. The availability of PHGC samples provides a unique opportunity to continue to develop deeper phenotypes on every PRRSV infected pig.
PMCID: PMC3108226 PMID: 21645311
19. TACE release of TNF-α mediates mechanotransduction-induced activation of p38 MAPK and myogenesis
Journal of cell science 2007;120(Pt 4):692-701.
Skeletal muscle responds to mechanical stimulation by activating p38 MAPK, a key signal for myogenesis. However, the mechanotransduction mechanism that activates p38 is unknown. Here we show that mechanical stimulation of myoblasts activates p38 and myogenesis through stimulating TNF-α release by TNF-α converting enzyme (TACE). In C2C12 or mouse primary myoblasts cultured in growth medium, static stretch activated p38 along with ERK1/2, JNK and AKT. Disrupting TNF-α signaling by TNF-α-neutralizing antibody or knocking out TNF-α receptors blocked stretch activation of p38, but not ERK1/2, JNK or AKT. Stretch also activated differentiation markers MEF2C, myogenin, p21 and myosin heavy chain in a TNF-α- and p38-dependent manner. Stretch stimulated the cleavage activity of TACE. Conversely, TACE inhibitor TAPI or TACE siRNA abolished stretch activation of p38. In addition, conditioned medium from stretched myoblast cultures activated p38 in unstretched myoblasts, which required TACE activity in the donor myoblasts, and TNF-α receptors in the recipient myoblasts. These results indicate that posttranscriptional activation of TACE mediates the mechanotransduction that activates p38-dependent myogenesis via the release of TNF-α.
PMCID: PMC3099537 PMID: 17264149
Stretch; Myogenesis; p38 MAPK; TACE; TNF-α
20. Overload-Induced Skeletal Muscle Extracellular Matrix Remodeling And Myofiber Growth in Mice Lacking IL-6
Acta physiologica (Oxford, England) 2009;197(4):321-332.
Overloading healthy skeletal muscle produces myofiber hypertrophy and extracellular matrix remodeling, and these processes are thought to be interdependent for producing muscle growth. Inflammatory cytokine interleukin-6 (IL-6) gene expression is induced in overloaded skeletal muscle, and the loss of this IL-6 induction can attenuate the hypertrophic response to overload. Although the overload induction of IL-6 in skeletal muscle may be an important regulator of inflammatory processes and satellite cell proliferation, less is known about its role in the regulation of extracellular matrix remodeling. The purpose of the current study was to examine if overload-induced extracellular matrix remodeling, muscle growth, and associated gene expression were altered in mice that lack IL-6, when compared to wild-type mice.
Male C57/BL6 (WT) and C57/BL6 × IL-6-/- (IL-6-/-) mice (10 wks of age) were assigned to either a sham control or synergist ablation overload (OV) treatments for 3 or 21 days.
Plantaris muscle mass increased 59% in WT and 116% in IL-6-/- mice after 21d OV. Myofiber CSA was also increased by 21d OV in both WT and IL-6-/- mice. Overload induced a 2-fold greater increase in the volume of non-contractile tissue in IL-6-/- muscle as compared to WT. Overload also induced a significantly greater accumulation of hydroxyproline and procollagen-1 mRNA in IL-6-/- muscle, when compared to WT muscle after 21d OV. TGF-β and IGF-1 mRNA expression were also induced to a greater extent in IL-6-/- muscle when compared to WT muscle after 21d OV. There was no effect of IL-6 loss on the induction of myogenin, and cyclin D1 mRNA expression after 3d OV. However, MyoD mRNA expression in 3d OV IL-6-/- muscle was attenuated when compared to WT overload mice.
IL-6 appears to be necessary for the normal regulation of extracellular matrix remodeling during overload-induced growth.
PMCID: PMC3044433 PMID: 19681796
functional overload; extracellular matrix; inflammation; transforming growth factor beta
21. Development and Application of Bovine and Porcine Oligonucleotide Arrays with Protein-Based Annotation
The design of oligonucleotide sequences for the detection of gene expression in species with disparate volumes of genome and EST sequence information has been broadly studied. However, a congruous strategy has yet to emerge to allow the design of sensitive and specific gene expression detection probes. This study explores the use of a phylogenomic approach to align transcribed sequences to vertebrate protein sequences for the detection of gene families to design genomewide 70-mer oligonucleotide probe sequences for bovine and porcine. The bovine array contains 23,580 probes that target the transcripts of 16,341 genes, about 72% of the total number of bovine genes. The porcine array contains 19,980 probes targeting 15,204 genes, about 76% of the genes in the Ensembl annotation of the pig genome. An initial experiment using the bovine array demonstrates the specificity and sensitivity of the array.
PMCID: PMC3010673 PMID: 21197395
22. Myostatin genotype regulates muscle-specific miRNA expression in mouse pectoralis muscle
BMC Research Notes 2010;3:297.
Loss of functional Myostatin results in a dramatic increase in skeletal muscle mass. It is unknown what role miRNAs play in Myostatin mediated repression of skeletal muscle mass. We hypothesized that Myostatin genotype would be associated with the differential expression of miRNAs in skeletal muscle.
Loss of functional Myostatin resulted in a significant increase (p < .001) in miR-1, miR-133a, miR-133b, and miR-206 expression. In contrast, Myostatin genotype had no effect (P > .2) on miR-24 expression level. Myostatin genotype did not affect the expression level of MyoD or Myogenin (P > 0.5).
Myostatin may regulates the expression of miRNAs such as miR-133a, miR-133b, miR-1, and miR-206 in skeletal muscle as it has been observed that the expression of those miRNAs are significantly higher in myostatin null mice compared to wild type and heterozygous mice. In contrast, expression of myogenic factors such as MyoD or Myogenin has not been affected by myostatin in the muscle tissue.
PMCID: PMC2992544 PMID: 21070642
24. Skeletal Muscle Stem Cells from Animals I. Basic Cell Biology
Skeletal muscle stem cells from food-producing animals are of interest to agricultural life scientists seeking to develop a better understanding of the molecular regulation of lean tissue (skeletal muscle protein hypertrophy) and intramuscular fat (marbling) development. Enhanced understanding of muscle stem cell biology and function is essential for developing technologies and strategies to augment the metabolic efficiency and muscle hypertrophy of growing animals potentially leading to greater efficiency and reduced environmental impacts of animal production, while concomitantly improving product uniformity and consumer acceptance and enjoyment of muscle foods.
PMCID: PMC2935669 PMID: 20827399
Skeletal muscle stem cells; Satellite cells; Adipocytes; Adipofibroblasts; Embryogenesis; Postnatal myogenesis.
25. Lipid metabolism, adipocyte depot physiology and utilization of meat animals as experimental models for metabolic research
Meat animals are unique as experimental models for both lipid metabolism and adipocyte studies because of their direct economic value for animal production. This paper discusses the principles that regulate adipogenesis in major meat animals (beef cattle, dairy cattle, and pigs), the definition of adipose depot-specific regulation of lipid metabolism or adipogenesis, and introduces the potential value of these animals as models for metabolic research including mammary biology and the ontogeny of fatty livers.
PMCID: PMC2990072 PMID: 21103072
Meat animals; lipid metabolism; adipose depots; adipocytes; adipogenesis
Results 1-25 (27)
|
__label__1
| 0.842114
|
/ |
Decentralizing Tokyo may save the nation
Now it’s suddenly back. On April 14, Sankei Shimbun reported on a bipartisan meeting of national politicians in the Diet to set up fukutoshin (auxiliary capitals) that can take over if Tokyo is hit by a major natural disaster or terrorist attack. Some 200 lawmakers attended the meeting and agreed that construction must begin as soon as possible, by the end of the year at the latest. The urgency of such a task was underlined by Kobe University seismologist Katsuhiko Ishibashi, who warned at the meeting that if a major earthquake struck the Tokai region and damaged the Hamaoka nuclear power plant in Shizuoka Prefecture, Tokyo, which is less than 100 kilometers away, would have to be evacuated.
More than one auxiliary capital is preferable, but among the candidate locations the favorite seems to be Itami Airport in Osaka, a decision that should please Hashimoto, who wants to close Itami, once the region’s international airport, in order to boost the fortunes of the newer Kansai International Airport. A bill has been submitted to set up a special economic district for the auxiliary capital so that planning and construction can begin.
But while there is certainly a need to have government functions reproduced somewhere outside of Tokyo, there are some people who believe it is not enough. In an opinion piece in the Asahi Shimbun, Mitsushi Koyama, the president of food company Bansho, says that full-scale decentralization of Tokyo should be the goal. He uses the expected shortage of electricity this summer to show how too much of the nation’s resources are used for Tokyo and the surrounding regions. The area covered by Tokyo Electric Power Co. usually needs between 55 and 60 million kilowatts of power in the summer. None of the other nine regional power companies requires more than 20 million kilowatts at any one time.
But even if the government was moved out of Tokyo, Koyama doesn’t believe it’s enough. As he points out, only 2.8 percent of Tokyo’s workers toil in the public sector, and the old theory that private sector companies would follow the government seems less supportable with the advent of the Internet. If the government wants to promote decentralization, it should directly encourage companies to move out of Tokyo. There’s no reason for the Internet shopping mall Rakuten to have its headquarters in Roppongi. It can function anywhere. Japan has an excellent nationwide transportation network and high-speed communications system, so businesses can take advantage of regional characteristics.
Even Okinawa has special merits: All Nippon Airways has developed Naha Airport into a cargo hub for all of eastern Asia, so companies that sell parts to that area of the world could reduce costs if they relocated factories or distribution centers to Okinawa. The Mainichi Shimbun suggested Tokyo companies move to the Tohoku region in order to help it recover more quickly.
Shortly after the earthquake, some companies did move their offices out of the capital, but only temporarily. Under those circumstances, “leaving Tokyo” was seen as a negative thing. Koyama says business groups such as Nippon Keidanren (Japan Federation of Economic Organizations) should promote leaving Tokyo in a positive light. A 47-year-old man who wrote a letter to the Asahi expressed similar ideas but added he didn’t think the government could be counted on to make decentralization happen. Despite the concerted push to find an auxiliary capital, the Diet on April 15 passed a bill to give tax breaks to large corporations that plan redevelopment activities in large cities, including Tokyo, where all the large corporations are headquartered.
Ishihara is also an obstacle. During his recent reelection campaign, he supported greater disaster prevention capabilities for the city rather than decentralization. The governor, who has repeatedly said his political vision is national, wants to change Japan from his vantage point of Tokyo, thus indicating Tokyo is the nation. By that logic, if Tokyo falls, so does Japan.
Philip Brasor blogs at philipbrasor.com.
|
__label__1
| 0.924723
|
The Nation
School spending
Struggle to cover school expenses intensifies: survey
Rising debt, lower incomes and rising prices have combined to add pressure on parents as they buy school supplies such as uniforms, shoes and books, according to a survey by the University of the Thai Chamber of Commerce (UTCC).
"Parents are complaining that they are spending more for fewer goods. This is an indicator of the rising price of products," said Vachira Kunthawethep, a UTCC economist.
Based on a sample size of 1,254 parents, 51 per cent said they had to spend more for their child's education this year, and 50.1 per cent said they got less for their money than last year. Some 76 per cent of those surveyed said they had to spend more for clothes this year.
Vachira said that because of the rising cost of living and lower incomes, parents this year had turned to loans outside the banking system to cover school expenses, which average Bt6,900-Bt7,000 per child. Many urged the government to provide some financial help for their child's education.
Spending during Visakha Bucha Day next Tuesday is also expected to be lower, according to the UTCC survey.
A total of 43.4 per cent of respondents believed that there would be less celebrating during this Buddhist holiday because of rising goods prices (46.9 per cent), a worsening economy (41.1 per cent) and rising fuel prices (12 per cent).
However, 87.7 per cent said they would still go to make merit at the temple; 67.4 said they would use their money for making merit but only 7.3 per cent of people in Bangkok said they would spend to return home to their provinces.
Comments conditions
|
__label__1
| 0.995043
|
National Capital Consortium
Discrimination or Harassment Uninvited and unwelcomed verbal or physical conduct directed at an employee because of sex, religion, ethnicity or beliefs. (Examples include: bias in hiring, assignments, promotions, educational decisions; unfair compensation; inappropriate language; wrongful termination). Retaliation or retribution.
Duty Hours Violation ACGME duty hours policy violated when: duty hours exceeded ACGME requirement of no more than 80 hours per week, averaged over a four-week period, inclusive of all in-house call activities; resident or fellow was not provided 1 day in 7 free from all educational and clinicl responsibilities, averaged over 4-week period; trainee was not provided a 10-hour time period between all daily duty periods and after in-house call; In-house call occured more frequently than every third night, averaged over a 4-week period; or continuous duty on-site exceeded 24 consecutive hours.
Gifts and Entertainment Refers to the solicitation or acceptance of items from residents, family members, referral sources, or other third parties
GME Program Concerns Concerns related specifically to program effectiveness. (Examples would include goals and objectives not provided or not met for a particular rotation, learning compromised by the presence of too many trainees not part of your program, inability to raise problems or concerns without fear of intimidation or retaliation, clinical education disrupted by excessive service obligations etc.)
Health Insurance Portability and Accountability Act This Category should be selected if there is a concern with the improper use or disclosure of Protected Health Information. Protected Health Information is information that:
(1) is created or received by a health care provider, health plan, public health authority, employer, life insurer, school or university, or health care clearinghouse; and (2) relates to the past, present, or future physical or mental health or condition of an individual; the provision of health care to an individual; or the past, present, or future payment for the provision of health care to an individual; and (i) that identifies the individual; or (ii) for which there is a reasonable basis to believe the information can be used to identify the individual.
Patient Abuse/Physical Intentionally causing harm to a patient or neglecting a patient whom needs medical attention or assistance.
Patient Abuse/Verbal Any language directed at a patient by an employee, which would be offensive (swearing), or language used to berate, belittle, or otherwise cause the patient to feel intimidated or threatened.
Patient Care Failure of those responsible for patient care, to properly attend to the every day needs of a patient(s).
Patient's Rights Failures of those responsible for patient care to allow a patient(s) to follow/complete his/her daily routine, i.e. bathing, watching television, smoking, etc.
Safety, Health and the Environment Failure to provide a safe working environment or training required by company policies; failure to report accidents, etc. concealing of actual or potential environmental damage; failure to comply with environmental laws.
Scientific Misconduct Fabrication, falsification, plagiarism, or other practices that seriously deviate from those that are commonly accepted within the scientific community for proposing, conducting, or reporting research. Fabrication is making up data or results and recording or reprinting them. Falsification is manipulating research materials, equipment or processes, or changing or omitting data or results, such that the research is not accurately reported in the research record. Plagiarism is the appropriation of another person's ideas, processes, results, or words without giving appropriate credit.
Unauthorized/Fraudulent Use of Company facilities and equipment The misuse/abuse of Company Support Services, equipment, or assets.
|
__label__1
| 0.977486
|
Ocean of Dharma
Being Meticulous is Not Based on Fear
Cessation and salvation come to you as you become a reasonable person. You become reasonable and meticulous because you cease to be sloppy and careless. Therefore, there is a sense of relief. Meticulousness is exemplified by oryoki practice, a formal style of serving and eating food that has its origins in Zen Buddhism. In this practice you are aware of everything that is being done, every move. At the same time, you are not uptight, for once you become self-conscious, you begin to forget the oryoki procedures. This logic also applies to keeping your room tidy, taking care of your clothing, taking care of your lifestyle altogether. Being meticulous is not based on fear; it is based on natural mindfulness.
|
__label__1
| 0.595382
|
Search tips
Search criteria
Results 1-25 (1022161)
Clipboard (0)
Related Articles
Biology Direct 2006;1:22.
Ever since the discovery of 'genes in pieces' and mRNA splicing in eukaryotes, origin and evolution of spliceosomal introns have been considered within the conceptual framework of the 'introns early' versus 'introns late' debate. The 'introns early' hypothesis, which is closely linked to the so-called exon theory of gene evolution, posits that protein-coding genes were interrupted by numerous introns even at the earliest stages of life's evolution and that introns played a major role in the origin of proteins by facilitating recombination of sequences coding for small protein/peptide modules. Under this scenario, the absence of spliceosomal introns in prokaryotes is considered to be a result of "genome streamlining". The 'introns late' hypothesis counters that spliceosomal introns emerged only in eukaryotes, and moreover, have been inserted into protein-coding genes continuously throughout the evolution of eukaryotes. Beyond the formal dilemma, the more substantial side of this debate has to do with possible roles of introns in the evolution of eukaryotes.
I argue that several lines of evidence now suggest a coherent solution to the introns-early versus introns-late debate, and the emerging picture of intron evolution integrates aspects of both views although, formally, there seems to be no support for the original version of introns-early. Firstly, there is growing evidence that spliceosomal introns evolved from group II self-splicing introns which are present, usually, in small numbers, in many bacteria, and probably, moved into the evolving eukaryotic genome from the α-proteobacterial progenitor of the mitochondria. Secondly, the concept of a primordial pool of 'virus-like' genetic elements implies that self-splicing introns are among the most ancient genetic entities. Thirdly, reconstructions of the ancestral state of eukaryotic genes suggest that the last common ancestor of extant eukaryotes had an intron-rich genome. Thus, it appears that ancestors of spliceosomal introns, indeed, have existed since the earliest stages of life's evolution, in a formal agreement with the introns-early scenario. However, there is no evidence that these ancient introns ever became widespread before the emergence of eukaryotes, hence, the central tenet of introns-early, the role of introns in early evolution of proteins, has no support. However, the demonstration that numerous introns invaded eukaryotic genes at the outset of eukaryotic evolution and that subsequent intron gain has been limited in many eukaryotic lineages implicates introns as an ancestral feature of eukaryotic genomes and refutes radical versions of introns-late. Perhaps, most importantly, I argue that the intron invasion triggered other pivotal events of eukaryogenesis, including the emergence of the spliceosome, the nucleus, the linear chromosomes, the telomerase, and the ubiquitin signaling system. This concept of eukaryogenesis, in a sense, revives some tenets of the exon hypothesis, by assigning to introns crucial roles in eukaryotic evolutionary innovation.
The scenario of the origin and evolution of introns that is best compatible with the results of comparative genomics and theoretical considerations goes as follows: self-splicing introns since the earliest stages of life's evolution – numerous spliceosomal introns invading genes of the emerging eukaryote during eukaryogenesis – subsequent lineage-specific loss and gain of introns. The intron invasion, probably, spawned by the mitochondrial endosymbiont, might have critically contributed to the emergence of the principal features of the eukaryotic cell. This scenario combines aspects of the introns-early and introns-late views.
this article was reviewed by W. Ford Doolittle, James Darnell (nominated by W. Ford Doolittle), William Martin, and Anthony Poole.
PMCID: PMC1570339 PMID: 16907971
2. New Maximum Likelihood Estimators for Eukaryotic Intron Evolution
PLoS Computational Biology 2005;1(7):e79.
The evolution of spliceosomal introns remains poorly understood. Although many approaches have been used to infer intron evolution from the patterns of intron position conservation, the results to date have been contradictory. In this paper, we address the problem using a novel maximum likelihood method, which allows estimation of the frequency of intron insertion target sites, together with the rates of intron gain and loss. We analyzed the pattern of 10,044 introns (7,221 intron positions) in the conserved regions of 684 sets of orthologs from seven eukaryotes. We determined that there is an average of one target site per 11.86 base pairs (bp) (95% confidence interval, 9.27 to 14.39 bp). In addition, our results showed that: (i) overall intron gains are ~25% greater than intron losses, although specific patterns vary with time and lineage; (ii) parallel gains account for ~18.5% of shared intron positions; and (iii) reacquisition following loss accounts for ~0.5% of all intron positions. Our results should assist in resolving the long-standing problem of inferring the evolution of spliceosomal introns.
When did spliceosomal introns originate, and what is their role? These questions are the central subject of the introns-early versus introns-late debate. Inference of intron evolution from the pattern of intron position conservation is vital for resolving this debate. So far, different methods of two approaches, maximum parsimony (MP) and maximum likelihood (ML), have been developed, but the results are contradictory. The differences between previous ML results are due predominantly to differing assumptions concerning the frequency of target sites for intron insertion. This paper describes a new ML method that treats this frequency as a parameter requiring optimization. Using the pattern of intron position in conserved regions of 684 clusters of gene orthologs from seven eukaryotes, the authors found that, on average, there is one target site per ~12 base pairs. The results of intron evolution inferred using this optimal frequency are more definitive than previous ML results. Since the ML method is preferred to the MP one for large datasets, the current results should be the most reliable ones to date. The results show that during the course of evolution there have been slightly more intron gains than losses, and thus they favor introns-late. These results should shed new light on our understanding of intron evolution.
PMCID: PMC1323467 PMID: 16389300
3. Evolutionary Convergence on Highly-Conserved 3′ Intron Structures in Intron-Poor Eukaryotes and Insights into the Ancestral Eukaryotic Genome
PLoS Genetics 2008;4(8):e1000148.
The presence of spliceosomal introns in eukaryotes raises a range of questions about genomic evolution. Along with the fundamental mysteries of introns' initial proliferation and persistence, the evolutionary forces acting on intron sequences remain largely mysterious. Intron number varies across species from a few introns per genome to several introns per gene, and the elements of intron sequences directly implicated in splicing vary from degenerate to strict consensus motifs. We report a 50-species comparative genomic study of intron sequences across most eukaryotic groups. We find two broad and striking patterns. First, we find that some highly intron-poor lineages have undergone evolutionary convergence to strong 3′ consensus intron structures. This finding holds for both branch point sequence and distance between the branch point and the 3′ splice site. Interestingly, this difference appears to exist within the genomes of green alga of the genus Ostreococcus, which exhibit highly constrained intron sequences through most of the intron-poor genome, but not in one much more intron-dense genomic region. Second, we find evidence that ancestral genomes contained highly variable branch point sequences, similar to more complex modern intron-rich eukaryotic lineages. In addition, ancestral structures are likely to have included polyT tails similar to those in metazoans and plants, which we found in a variety of protist lineages. Intriguingly, intron structure evolution appears to be quite different across lineages experiencing different types of genome reduction: whereas lineages with very few introns tend towards highly regular intronic sequences, lineages with very short introns tend towards highly degenerate sequences. Together, these results attest to the complex nature of ancestral eukaryotic splicing, the qualitatively different evolutionary forces acting on intron structures across modern lineages, and the impressive evolutionary malleability of eukaryotic gene structures.
Author Summary
The spliceosomal introns that interrupt eukaryotic genes show great number and sequence variation across species, from the rare, highly uniform yeast introns to the ubiquitous and highly variable vertebrate intron sequences. The causes of these differences remain mysterious. We studied sequences of intron branch points and 3′ termini in 50 eukaryotic species. All intron-rich species exhibit variable 3′ sequences. However, intron-poor species range from variable sequences, to uniform branch point motifs, to uniform branch point motifs in uniform positions along the intronic sequence. This is a more complex pattern than the clear relationship between intron number and 5′ intron sequence uniformity found previously. The correspondence of sequence uniformity and intron number extends to species of the green algal genus Ostreococcus, in which the single intron-rich genomic region shows far more variable intron sequences than in the otherwise intron-poor genome. We suggest that different concentrations of spliceosomal complexes may explain these differences. In addition, we report the existence of 3′ polyT tails in diverse eukaryotic protists, suggesting that this structure is ancestral. Together, these results underscore the complexity of ancestral eukaryotic splicing, the qualitatively different evolutionary forces acting on intron sequences in modern eukaryotes, and the impressive evolutionary malleability of eukaryotic genes.
PMCID: PMC2483917 PMID: 18688272
4. A Detailed History of Intron-rich Eukaryotic Ancestors Inferred from a Global Survey of 100 Complete Genomes
PLoS Computational Biology 2011;7(9):e1002150.
Protein-coding genes in eukaryotes are interrupted by introns, but intron densities widely differ between eukaryotic lineages. Vertebrates, some invertebrates and green plants have intron-rich genes, with 6–7 introns per kilobase of coding sequence, whereas most of the other eukaryotes have intron-poor genes. We reconstructed the history of intron gain and loss using a probabilistic Markov model (Markov Chain Monte Carlo, MCMC) on 245 orthologous genes from 99 genomes representing the three of the five supergroups of eukaryotes for which multiple genome sequences are available. Intron-rich ancestors are confidently reconstructed for each major group, with 53 to 74% of the human intron density inferred with 95% confidence for the Last Eukaryotic Common Ancestor (LECA). The results of the MCMC reconstruction are compared with the reconstructions obtained using Maximum Likelihood (ML) and Dollo parsimony methods. An excellent agreement between the MCMC and ML inferences is demonstrated whereas Dollo parsimony introduces a noticeable bias in the estimations, typically yielding lower ancestral intron densities than MCMC and ML. Evolution of eukaryotic genes was dominated by intron loss, with substantial gain only at the bases of several major branches including plants and animals. The highest intron density, 120 to 130% of the human value, is inferred for the last common ancestor of animals. The reconstruction shows that the entire line of descent from LECA to mammals was intron-rich, a state conducive to the evolution of alternative splicing.
Author Summary
In eukaryotes, protein-coding genes are interrupted by non-coding introns. The intron densities widely differ, from 6–7 introns per kilobase of coding sequence in vertebrates, some invertebrates and plants, to only a few introns across the entire genome in many unicellular forms. We applied a robust statistical methodology, Markov Chain Monte Carlo, to reconstruct the history of intron gain and loss throughout the evolution of eukaryotes using a set of 245 homologous genes from 99 genomes that represent the diversity of eukaryotes. Intron-rich ancestors were confidently inferred for each major eukaryotic group including 53% to 74% of the human intron density for the last eukaryotic common ancestor, and 120% to 130% of the human value for the last common ancestor of animals. Evolution of eukaryotic genes involved primarily intron loss, with substantial gain only at the bases of several major branches including plants and animals. Thus, the common ancestor of all extant eukaryotes was a complex organism with a gene architecture resembling those in multicellular organisms. The line of descent from the last common ancestor to mammals was an uninterrupted intron-rich state that, given the error-prone splicing in intron-rich organisms, was conducive to the elaboration of functional alternative splicing.
PMCID: PMC3174169 PMID: 21935348
5. Origin and evolution of spliceosomal introns
Biology Direct 2012;7:11.
Evolution of exon-intron structure of eukaryotic genes has been a matter of long-standing, intensive debate. The introns-early concept, later rebranded ‘introns first’ held that protein-coding genes were interrupted by numerous introns even at the earliest stages of life's evolution and that introns played a major role in the origin of proteins by facilitating recombination of sequences coding for small protein/peptide modules. The introns-late concept held that introns emerged only in eukaryotes and new introns have been accumulating continuously throughout eukaryotic evolution. Analysis of orthologous genes from completely sequenced eukaryotic genomes revealed numerous shared intron positions in orthologous genes from animals and plants and even between animals, plants and protists, suggesting that many ancestral introns have persisted since the last eukaryotic common ancestor (LECA). Reconstructions of intron gain and loss using the growing collection of genomes of diverse eukaryotes and increasingly advanced probabilistic models convincingly show that the LECA and the ancestors of each eukaryotic supergroup had intron-rich genes, with intron densities comparable to those in the most intron-rich modern genomes such as those of vertebrates. The subsequent evolution in most lineages of eukaryotes involved primarily loss of introns, with only a few episodes of substantial intron gain that might have accompanied major evolutionary innovations such as the origin of metazoa. The original invasion of self-splicing Group II introns, presumably originating from the mitochondrial endosymbiont, into the genome of the emerging eukaryote might have been a key factor of eukaryogenesis that in particular triggered the origin of endomembranes and the nucleus. Conversely, splicing errors gave rise to alternative splicing, a major contribution to the biological complexity of multicellular eukaryotes. There is no indication that any prokaryote has ever possessed a spliceosome or introns in protein-coding genes, other than relatively rare mobile self-splicing introns. Thus, the introns-first scenario is not supported by any evidence but exon-intron structure of protein-coding genes appears to have evolved concomitantly with the eukaryotic cell, and introns were a major factor of evolution throughout the history of eukaryotes. This article was reviewed by I. King Jordan, Manuel Irimia (nominated by Anthony Poole), Tobias Mourier (nominated by Anthony Poole), and Fyodor Kondrashov. For the complete reports, see the Reviewers’ Reports section.
PMCID: PMC3488318 PMID: 22507701
Intron sliding; Intron gain; Intron loss; Spliceosome; Splicing signals; Evolution of exon/intron structure; Alternative splicing; Phylogenetic trees; Mobile domains; Eukaryotic ancestor
6. Recurrent Loss of Specific Introns during Angiosperm Evolution
PLoS Genetics 2014;10(12):e1004843.
Numerous instances of presence/absence variations for introns have been documented in eukaryotes, and some cases of recurrent loss of the same intron have been suggested. However, there has been no comprehensive or phylogenetically deep analysis of recurrent intron loss. Of 883 cases of intron presence/absence variation that we detected in five sequenced grass genomes, 93 were confirmed as recurrent losses and the rest could be explained by single losses (652) or single gains (118). No case of recurrent intron gain was observed. Deep phylogenetic analysis often indicated that apparent intron gains were actually numerous independent losses of the same intron. Recurrent loss exhibited extreme non-randomness, in that some introns were removed independently in many lineages. The two larger genomes, maize and sorghum, were found to have a higher rate of both recurrent loss and overall loss and/or gain than foxtail millet, rice or Brachypodium. Adjacent introns and small introns were found to be preferentially lost. Intron loss genes exhibited a high frequency of germ line or early embryogenesis expression. In addition, flanking exon A+T-richness and intron TG/CG ratios were higher in retained introns. This last result suggests that epigenetic status, as evidenced by a loss of methylated CG dinucleotides, may play a role in the process of intron loss. This study provides the first comprehensive analysis of recurrent intron loss, makes a series of novel findings on the patterns of recurrent intron loss during the evolution of the grass family, and provides insight into the molecular mechanism(s) underlying intron loss.
Author Summary
The spliceosomal introns are nucleotide sequences that interrupt coding regions of eukaryotic genes and are removed by RNA splicing after transcription. Recent studies have reported several examples of possible recurrent intron loss or gain, i.e., introns that are independently removed from or inserted into the identical sites more than once in an investigated phylogeny. However, the frequency, evolutionary patterns or other characteristics of recurrent intron turnover remain unknown. We provide results for the first comprehensive analysis of recurrent intron turnover within a plant family and show that recurrent intron loss represents a considerable portion of all intron losses identified and intron loss events far outnumber intron gain events. We also demonstrate that recurrent intron loss is non-random, affecting only a small number of introns that are repeatedly lost, and that different lineages show significantly different rates of intron loss. Our results suggest a possible role of DNA methylation in the process of intron loss. Moreover, this study provides strong support for the model of intron loss by reverse transcriptase mediated conversion of genes by their processed mRNA transcripts.
PMCID: PMC4256211 PMID: 25474210
7. Effects of Taxon Sampling in Reconstructions of Intron Evolution
Introns comprise a considerable portion of eukaryotic genomes; however, their evolution is understudied. Numerous works of the last years largely disagree on many aspects of intron evolution. Interpretation of these differences is hindered because different algorithms and taxon sampling strategies were used. Here, we present the first attempt of a systematic evaluation of the effects of taxon sampling on popular intron evolution estimation algorithms. Using the “taxon jackknife” method, we compared the effect of taxon sampling on the behavior of intron evolution inferring algorithms. We show that taxon sampling can dramatically affect the inferences and identify conditions where algorithms are prone to systematic errors. Presence or absence of some key species is often more important than the taxon sampling size alone. Criteria of representativeness of the taxonomic sampling for reliable reconstructions are outlined. Presence of the deep-branching species with relatively high intron density is more important than sheer number of species. According to these criteria, currently available genomic databases are representative enough to provide reliable inferences of the intron evolution in animals, land plants, and fungi, but they underrepresent many groups of unicellular eukaryotes, including the well-studied Alveolata.
PMCID: PMC3647540 PMID: 23671844
8. Sm/Lsm Genes Provide a Glimpse into the Early Evolution of the Spliceosome
PLoS Computational Biology 2009;5(3):e1000315.
The spliceosome, a sophisticated molecular machine involved in the removal of intervening sequences from the coding sections of eukaryotic genes, appeared and subsequently evolved rapidly during the early stages of eukaryotic evolution. The last eukaryotic common ancestor (LECA) had both complex spliceosomal machinery and some spliceosomal introns, yet little is known about the early stages of evolution of the spliceosomal apparatus. The Sm/Lsm family of proteins has been suggested as one of the earliest components of the emerging spliceosome and hence provides a first in-depth glimpse into the evolving spliceosomal apparatus. An analysis of 335 Sm and Sm-like genes from 80 species across all three kingdoms of life reveals two significant observations. First, the eukaryotic Sm/Lsm family underwent two rapid waves of duplication with subsequent divergence resulting in 14 distinct genes. Each wave resulted in a more sophisticated spliceosome, reflecting a possible jump in the complexity of the evolving eukaryotic cell. Second, an unusually high degree of conservation in intron positions is observed within individual orthologous Sm/Lsm genes and between some of the Sm/Lsm paralogs. This suggests that functional spliceosomal introns existed before the emergence of the complete Sm/Lsm family of proteins; hence, spliceosomal machinery with considerably fewer components than today's spliceosome was already functional.
Author Summary
The spliceosome is a complex molecular machine that removes intervening sequences (introns) from mRNAs. It is unique to eukaryotes. Although prokaryotes have self-splicing introns, they completely lack spliceosomal introns and the spliceosome itself. Yet even the simplest eukaryotic organisms have introns and a rather complex spliceosomal apparatus. Little is known about how this amazing machine rapidly evolved in early eukaryotes. Here, we attempt to reconstruct a part of this evolutionary process using one of the most fundamental components of the spliceosome—the Sm and Lsm family of proteins. Using sequence and structure analysis as well as the analysis of the intron positions in Sm and Lsm genes in conjunction with a wealth of published data, we propose a plausible scenario for some aspects of spliceosomal evolution. In particular, we suggest that the Lsm family of genes could have been the first and the most essential component that allowed rudimentary splicing of early spliceosomal introns. Extensive duplications of Lsm genes and the later rise of the Sm gene family likely reflect a gradual increase in complexity of the spliceosome.
PMCID: PMC2650416 PMID: 19282982
9. Nonsense-Mediated Decay Enables Intron Gain in Drosophila
PLoS Genetics 2010;6(1):e1000819.
Intron number varies considerably among genomes, but despite their fundamental importance, the mutational mechanisms and evolutionary processes underlying the expansion of intron number remain unknown. Here we show that Drosophila, in contrast to most eukaryotic lineages, is still undergoing a dramatic rate of intron gain. These novel introns carry significantly weaker splice sites that may impede their identification by the spliceosome. Novel introns are more likely to encode a premature termination codon (PTC), indicating that nonsense-mediated decay (NMD) functions as a backup for weak splicing of new introns. Our data suggest that new introns originate when genomic insertions with weak splice sites are hidden from selection by NMD. This mechanism reduces the sequence requirement imposed on novel introns and implies that the capacity of the spliceosome to recognize weak splice sites was a prerequisite for intron gain during eukaryotic evolution.
Author Summary
The surprising observation 30 years ago that genes are interrupted by non-coding introns changed our view of gene architecture. Intron number varies dramatically among species; ranging from nine introns/gene in humans to less than one in some simple eukyarotes. Here we ask where new introns come from and how they are maintained in a population. We find that novel introns do not arise from pre-existing introns, although the mechanisms that generate novel introns remain unclear. We also show that novel introns carry only weak signals for their identification and removal, and therefore depend on nonsense-mediated decay (NMD). NMD maintains RNA quality control by degrading transcripts that have not been spliced properly. We propose that NMD shelters novel introns from natural selection. This increases the likelihood that a novel intron will rise in frequency and be maintained within a population, thus increasing the rate of intron gain.
PMCID: PMC2809761 PMID: 20107520
10. Phase distribution of spliceosomal introns: implications for intron origin
The origin of spliceosomal introns is the central subject of the introns-early versus introns-late debate. The distribution of intron phases is non-uniform, with an excess of phase-0 introns. Introns-early explains this by speculating that a fraction of present-day introns were present between minigenes in the progenote and therefore must lie in phase-0. In contrast, introns-late predicts that the nonuniformity of intron phase distribution reflects the nonrandomness of intron insertions.
In this paper, we tested the two theories using analyses of intron phase distribution. We inferred the evolution of intron phase distribution from a dataset of 684 gene orthologs from seven eukaryotes using a maximum likelihood method. We also tested whether the observed intron phase distributions from 10 eukaryotes can be explained by intron insertions on a genome-wide scale. In contrast to the prediction of introns-early, the inferred evolution of intron phase distribution showed that the proportion of phase-0 introns increased over evolution. Consistent with introns-late, the observed intron phase distributions matched those predicted by an intron insertion model quite well.
Our results strongly support the introns-late hypothesis of the origin of spliceosomal introns.
PMCID: PMC1574350 PMID: 16959043
11. Comparative genomic analysis of fungal genomes reveals intron-rich ancestors
Genome Biology 2007;8(10):R223.
Analysis of intron gain and loss in fungal genomes provides support for an intron-rich fungus-animal ancestor.
Eukaryotic protein-coding genes are interrupted by spliceosomal introns, which are removed from transcripts before protein translation. Many facets of spliceosomal intron evolution, including age, mechanisms of origins, the role of natural selection, and the causes of the vast differences in intron number between eukaryotic species, remain debated. Genome sequencing and comparative analysis has made possible whole genome analysis of intron evolution to address these questions.
We analyzed intron positions in 1,161 sets of orthologous genes across 25 eukaryotic species. We find strong support for an intron-rich fungus-animal ancestor, with more than four introns per kilobase, comparable to the highest known modern intron densities. Indeed, the fungus-animal ancestor is estimated to have had more introns than any of the extant fungi in this study. Thus, subsequent fungal evolution has been characterized by widespread and recurrent intron loss occurring in all fungal clades. These results reconcile three previously proposed methods for estimation of ancestral intron number, which previously gave very different estimates of ancestral intron number for eight eukaryotic species, as well as a fourth more recent method. We do not find a clear inverse correspondence between rates of intron loss and gain, contrary to the predictions of selection-based proposals for interspecific differences in intron number.
Our results underscore the high intron density of eukaryotic ancestors and the widespread importance of intron loss through eukaryotic evolution.
PMCID: PMC2246297 PMID: 17949488
12. Metabolic modeling of endosymbiont genome reduction on a temporal scale
This study explores the order in which individual metabolic genes are lost in an in silico evolutionary process leading from the metabolic network of Eschericia coli to that of the genome-reduced endosymbiont Buchnera aphidicola.
Simulating the reductive evolutionary process under several growth conditions, a remarkable correlation between in silico and phylogenetically reconstructed gene loss time is obtained.A gene's k-robustness (its depth of backups) is prime determinant of its loss time.In silico gene loss time is a better predictor of their actual loss times than genomic features and network properties.Simulating the reductive evolutionary process by the loss of large blocks followed by single-gene deletions, as known to occur in evolution, yields a remarkable correspondence with the phylogenetic reconstruction and the block loss reported in the literature.
An open fundamental challenge in Systems Biology is whether a genome-scale model can predict patterns of genome evolution by realistically accounting for the associated biochemical constraints. In this study, we explore the order in which individual genes are lost in an in silico evolutionary process, leading from the metabolic network of Eschericia coli to that of the endosymbiont Buchnera aphidicola.
To evaluate the in silico gene loss time, we repeated the reductive evolutionary process introduced by Pál et al (2006), denoting the in silico deletion time of a gene in a single run of the reductive evolutionary process as the number of genes deleted before its own deletion occurred. By comparing the in silico evaluations of the gene loss time to that obtained by a phylogenetic reconstruction (Figure 1), we could evaluate the ability of an in silico process to predict temporal patterns of genome reduction. Applying this procedure on a literature-based viable media, we obtained a mean Spearman's correlation of 0.46 (53% of the maximal correlation, empirical P-value <9.9e−4) between in silico and phylogenetically reconstructed loss times. In order to provide an upper bound on evolutionary necessity stemming from metabolic constraints, we searched the space of potential growth media and biomass functions via a simulated annealing search algorithm aimed at identifying an environment/biomass function that maximizes the target correlation between in silico and reconstructed loss times. Simulating the reductive evolutionary process under the growth conditions and biomass function obtained in this process, we managed to improve the correlation between in silico and reconstructed loss times to a mean Spearman's correlation of 0.54 (63% of the maximal correlation, empirical P-value <9.9e−4, Figure 3).
Examining the dependency of the predicted loss time of each gene on its intrinsic network-level properties we find a very strong inverse Spearman's correlation of −0.84 (empirical P-value <9.9e−4) between the order of gene loss predicted in silico and the k-robustness levels of the genes, the latter denoting the depth of their functional backups in the network (Deutscher et al, 2006). Moreover, in order to examine whether the relative loss time of a gene is influenced by its functional dependencies with other genes, we performed a flux-coupling analysis and identified pairs of reactions whose activities asymmetrically depend on each other, i.e., are directionally coupled (Burgard et al, 2004). We find that genes encoding reactions whose activity is needed for activating the other reaction (and not vice versa) have a tendency to be lost later, as one would expect (binomial P-value <1e−14).
To assess the scale of these results, we examined as a control how well genomic features and network properties predict the phylogenetically reconstructed gene loss times. We examined the dependency of the latter on several factors that are known be inversely correlated with the propensity of a gene to be lost (Brinza et al, 2009; Delmotte et al, 2006; Tamames et al, 2007), including the genes' mRNA levels, tAI values (Covert et al, 2004; Reis et al, 2004; Sharp and Li, 1987; Tuller et al, 2010a) and the number of partners the gene products have in a protein–protein interaction network. Remarkably, these genomic features yield considerably lower Spearman's correlation than that obtained by the in silico simulations. Moreover, multiply regressing the loss times from the phylogenetic reconstruction on the in silico gene loss time predictions and the genomic and network variables, we found that the (normalized) coefficient of the in silico predictions in the regression is much higher than those of the genomic features, further testifying to the considerable independent predictive power of the metabolic model.
Finally, simulating the evolutionary process as large block deletions at first followed by single-gene deletions as is thought to occur in evolution (Moran and Mira, 2001; van Ham et al, 2003), a remarkable correspondence with the phylogenetic reconstruction was found. Namely, we find that after a certain amount of genes are deleted from the genome, no further block deletions can occur due to the increasing density of essential genes. Notably, the maximum amount of genes that can be deleted in blocks (i.e., until no more blocks can be deleted) corresponds to the number of genes appearing in our phylogenetic reconstruction from the LCA (last common ancestor of Buchnera and E. coli) to the LCSA (last common symbiotic ancestor, nodes 1–3 in Figure 1A), as described in the literature.
A fundamental challenge in Systems Biology is whether a cell-scale metabolic model can predict patterns of genome evolution by realistically accounting for associated biochemical constraints. Here, we study the order in which genes are lost in an in silico evolutionary process, leading from the metabolic network of Eschericia coli to that of the endosymbiont Buchnera aphidicola. We examine how this order correlates with the order by which the genes were actually lost, as estimated from a phylogenetic reconstruction. By optimizing this correlation across the space of potential growth and biomass conditions, we compute an upper bound estimate on the model's prediction accuracy (R=0.54). The model's network-based predictive ability outperforms predictions obtained using genomic features of individual genes, reflecting the effect of selection imposed by metabolic stoichiometric constraints. Thus, while the timing of gene loss might be expected to be a completely stochastic evolutionary process, remarkably, we find that metabolic considerations, on their own, make a marked 40% contribution to determining when such losses occur.
PMCID: PMC3094061 PMID: 21451589
constraint-based modeling; endosymbiont; evolution; metabolism
13. EREM: Parameter Estimation and Ancestral Reconstruction by Expectation-Maximization Algorithm for a Probabilistic Model of Genomic Binary Characters Evolution
Advances in Bioinformatics 2010;2010:167408.
Evolutionary binary characters are features of species or genes, indicating the absence (value zero) or presence (value one) of some property. Examples include eukaryotic gene architecture (the presence or absence of an intron in a particular locus), gene content, and morphological characters. In many studies, the acquisition of such binary characters is assumed to represent a rare evolutionary event, and consequently, their evolution is analyzed using various flavors of parsimony. However, when gain and loss of the character are not rare enough, a probabilistic analysis becomes essential. Here, we present a comprehensive probabilistic model to describe the evolution of binary characters on a bifurcating phylogenetic tree. A fast software tool, EREM, is provided, using maximum likelihood to estimate the parameters of the model and to reconstruct ancestral states (presence and absence in internal nodes) and events (gain and loss events along branches).
PMCID: PMC2866244 PMID: 20467467
14. Patterns of intron gain and conservation in eukaryotic genes
PMCID: PMC2151770 PMID: 17935625
15. Analysis of Ribosomal Protein Gene Structures: Implications for Intron Evolution
PLoS Genetics 2006;2(3):e25.
Many spliceosomal introns exist in the eukaryotic nuclear genome. Despite much research, the evolution of spliceosomal introns remains poorly understood. In this paper, we tried to gain insights into intron evolution from a novel perspective by comparing the gene structures of cytoplasmic ribosomal proteins (CRPs) and mitochondrial ribosomal proteins (MRPs), which are held to be of archaeal and bacterial origin, respectively. We analyzed 25 homologous pairs of CRP and MRP genes that together had a total of 527 intron positions. We found that all 12 of the intron positions shared by CRP and MRP genes resulted from parallel intron gains and none could be considered to be “conserved,” i.e., descendants of the same ancestor. This was supported further by the high frequency of proto-splice sites at these shared positions; proto-splice sites are proposed to be sites for intron insertion. Although we could not definitively disprove that spliceosomal introns were already present in the last universal common ancestor, our results lend more support to the idea that introns were gained late. At least, our results show that MRP genes were intronless at the time of endosymbiosis. The parallel intron gains between CRP and MRP genes accounted for 2.3% of total intron positions, which should provide a reliable estimate for future inferences of intron evolution.
Genes in eukaryotes are usually intervened by extra bits of DNA sequence, called introns, that have to be removed after the genes are transcribed into RNA. Why do introns exist in eukaryotic genes? What is the reason for the increased intron density in higher eukaryotes? There is much that is not known about introns. This research tries to clarify the evolutionary process by which introns arose by comparing the gene structures of two types of ribosomal proteins; one in cytoplasm and the other in mitochondria of the cell. Since cytoplasm and mitochondria are of archaeal and bacterial origin, respectively, cytoplasmic ribosomal proteins (CRPs) and mitochondrial ribosomal proteins (MRPs) are believed to diverge at the same time with the divergence of archaea and bacteria. Thus, a comparative analysis of CRP and MRP genes may reveal whether introns already existed at the last common ancestor of archaea and bacteria (introns-early) or whether they emerged late (introns-late). The results make it clear, at least, that all of the introns in MRP genes were gained during the course of eukaryotic evolution and therefore lend more support to the introns-late theory.
PMCID: PMC1386722 PMID: 16518464
16. Modeling the evolution dynamics of exon-intron structure with a general random fragmentation process
Most eukaryotic genes are interrupted by spliceosomal introns. The evolution of exon-intron structure remains mysterious despite rapid advance in genome sequencing technique. In this work, a novel approach is taken based on the assumptions that the evolution of exon-intron structure is a stochastic process, and that the characteristics of this process can be understood by examining its historical outcome, the present-day size distribution of internal translated exons (exon). Through the combination of simulation and modeling the size distribution of exons in different species, we propose a general random fragmentation process (GRFP) to characterize the evolution dynamics of exon-intron structure. This model accurately predicts the probability that an exon will be split by a new intron and the distribution of novel insertions along the length of the exon.
As the first observation from this model, we show that the chance for an exon to obtain an intron is proportional to its size to the 3rd power. We also show that such size dependence is nearly constant across gene, with the exception of the exons adjacent to the 5′ UTR. As the second conclusion from the model, we show that intron insertion loci follow a normal distribution with a mean of 0.5 (center of the exon) and a standard deviation of 0.11. Finally, we show that intron insertions within a gene are independent of each other for vertebrates, but are more negatively correlated for non-vertebrate. We use simulation to demonstrate that the negative correlation might result from significant intron loss during evolution, which could be explained by selection against multi-intron genes in these organisms.
The GRFP model suggests that intron gain is dynamic with a higher chance for longer exons; introns are inserted into exons randomly with the highest probability at the center of the exon. GRFP estimates that there are 78 introns in every 10 kb coding sequences for vertebrate genomes, agreeing with empirical observations. GRFP also estimates that there are significant intron losses in the evolution of non-vertebrate genomes, with extreme cases of around 57% intron loss in Drosophila melanogaster, 28% in Caenorhabditis elegans, and 24% in Oryza sativa.
PMCID: PMC3732091 PMID: 23448166
Evolution of exon-intron structure; General random fragmentation process; Simulation
17. Computational identification of functional introns: high positional conservation of introns that harbor RNA genes
Nucleic Acids Research 2013;41(11):5604-5613.
An appreciable fraction of introns is thought to have some function, but there is no obvious way to predict which specific intron is likely to be functional. We hypothesize that functional introns experience a different selection regime than non-functional ones and will therefore show distinct evolutionary histories. In particular, we expect functional introns to be more resistant to loss, and that this would be reflected in high conservation of their position with respect to the coding sequence. To test this hypothesis, we focused on introns whose function comes about from microRNAs and snoRNAs that are embedded within their sequence. We built a data set of orthologous genes across 28 eukaryotic species, reconstructed the evolutionary histories of their introns and compared functional introns with the rest of the introns. We found that, indeed, the position of microRNA- and snoRNA-bearing introns is significantly more conserved. In addition, we found that both families of RNA genes settled within introns early during metazoan evolution. We identified several easily computable intronic properties that can be used to detect functional introns in general, thereby suggesting a new strategy to pinpoint non-coding cellular functions.
PMCID: PMC3675471 PMID: 23605046
18. Metabolic network reconstruction of Chlamydomonas offers insight into light-driven algal metabolism
A comprehensive genome-scale metabolic network of Chlamydomonas reinhardtii, including a detailed account of light-driven metabolism, is reconstructed and validated. The model provides a new resource for research of C. reinhardtii metabolism and in algal biotechnology.
The genome-scale metabolic network of Chlamydomonas reinhardtii (iRC1080) was reconstructed, accounting for >32% of the estimated metabolic genes encoded in the genome, and including extensive details of lipid metabolic pathways.This is the first metabolic network to explicitly account for stoichiometry and wavelengths of metabolic photon usage, providing a new resource for research of C. reinhardtii metabolism and developments in algal biotechnology.Metabolic functional annotation and the largest transcript verification of a metabolic network to date was performed, at least partially verifying >90% of the transcripts accounted for in iRC1080. Analysis of the network supports hypotheses concerning the evolution of latent lipid pathways in C. reinhardtii, including very long-chain polyunsaturated fatty acid and ceramide synthesis pathways.A novel approach for modeling light-driven metabolism was developed that accounts for both light source intensity and spectral quality of emitted light. The constructs resulting from this approach, termed prism reactions, were shown to significantly improve the accuracy of model predictions, and their use was demonstrated for evaluation of light source efficiency and design.
Algae have garnered significant interest in recent years, especially for their potential application in biofuel production. The hallmark, model eukaryotic microalgae Chlamydomonas reinhardtii has been widely used to study photosynthesis, cell motility and phototaxis, cell wall biogenesis, and other fundamental cellular processes (Harris, 2001). Characterizing algal metabolism is key to engineering production strains and understanding photobiological phenomena. Based on extensive literature on C. reinhardtii metabolism, its genome sequence (Merchant et al, 2007), and gene functional annotation, we have reconstructed and experimentally validated the genome-scale metabolic network for this alga, iRC1080, the first network to account for detailed photon absorption permitting growth simulations under different light sources. iRC1080 accounts for 1080 genes, associated with 2190 reactions and 1068 unique metabolites and encompasses 83 subsystems distributed across 10 cellular compartments (Figure 1A). Its >32% coverage of estimated metabolic genes is a tremendous expansion over previous algal reconstructions (Boyle and Morgan, 2009; Manichaikul et al, 2009). The lipid metabolic pathways of iRC1080 are considerably expanded relative to existing networks, and chemical properties of all metabolites in these pathways are accounted for explicitly, providing sufficient detail to completely specify all individual molecular species: backbone molecule and stereochemical numbering of acyl-chain positions; acyl-chain length; and number, position, and cis–trans stereoisomerism of carbon–carbon double bonds. Such detail in lipid metabolism will be critical for model-driven metabolic engineering efforts.
We experimentally verified transcripts accounted for in the network under permissive growth conditions, detecting >90% of tested transcript models (Figure 1B) and providing validating evidence for the contents of iRC1080. We also analyzed the extent of transcript verification by specific metabolic subsystems. Some subsystems stood out as more poorly verified, including chloroplast and mitochondrial transport systems and sphingolipid metabolism, all of which exhibited <80% of transcripts detected, reflecting incomplete characterization of compartmental transporters and supporting a hypothesis of latent pathway evolution for ceramide synthesis in C. reinhardtii. Additional lines of evidence from the reconstruction effort similarly support this hypothesis including lack of ceramide synthetase and other annotation gaps downstream in sphingolipid metabolism. A similar hypothesis of latent pathway evolution was established for very long-chain fatty acids (VLCFAs) and their polyunsaturated analogs (VLCPUFAs) (Figure 1C), owing to the absence of this class of lipids in previous experimental measurements, lack of a candidate VLCFA elongase in the functional annotation, and additional downstream annotation gaps in arachidonic acid metabolism.
The network provides a detailed account of metabolic photon absorption by light-driven reactions, including photosystems I and II, light-dependent protochlorophyllide oxidoreductase, provitamin D3 photoconversion to vitamin D3, and rhodopsin photoisomerase; this network accounting permits the precise modeling of light-dependent metabolism. iRC1080 accounts for effective light spectral ranges through analysis of biochemical activity spectra (Figure 3A), either reaction activity or absorbance at varying light wavelengths. Defining effective spectral ranges associated with each photon-utilizing reaction enabled our network to model growth under different light sources via stoichiometric representation of the spectral composition of emitted light, termed prism reactions. Coefficients for different photon wavelengths in a prism reaction correspond to the ratios of photon flux in the defined effective spectral ranges to the total emitted photon flux from a given light source (Figure 3B). This approach distinguishes the amount of emitted photons that drive different metabolic reactions. We created prism reactions for most light sources that have been used in published studies for algal and plant growth including solar light, various light bulbs, and LEDs. We also included regulatory effects, resulting from lighting conditions insofar as published studies enabled. Light and dark conditions have been shown to affect metabolic enzyme activity in C. reinhardtii on multiple levels: transcriptional regulation, chloroplast RNA degradation, translational regulation, and thioredoxin-mediated enzyme regulation. Through application of our light model and prism reactions, we were able to closely recapitulate experimental growth measurements under solar, incandescent, and red LED lights. Through unbiased sampling, we were able to establish the tremendous statistical significance of the accuracy of growth predictions achievable through implementation of prism reactions. Finally, application of the photosynthetic model was demonstrated prospectively to evaluate light utilization efficiency under different light sources. The results suggest that, of the existing light sources, red LEDs provide the greatest efficiency, about three times as efficient as sunlight. Extending this analysis, the model was applied to design a maximally efficient LED spectrum for algal growth. The result was a 677-nm peak LED spectrum with a total incident photon flux of 360 μE/m2/s, suggesting that for the simple objective of maximizing growth efficiency, LED technology has already reached an effective theoretical optimum.
In summary, the C. reinhardtii metabolic network iRC1080 that we have reconstructed offers insight into the basic biology of this species and may be employed prospectively for genetic engineering design and light source design relevant to algal biotechnology. iRC1080 was used to analyze lipid metabolism and generate novel hypotheses about the evolution of latent pathways. The predictive capacity of metabolic models developed from iRC1080 was demonstrated in simulating mutant phenotypes and in evaluation of light source efficiency. Our network provides a broad knowledgebase of the biochemistry and genomics underlying global metabolism of a photoautotroph, and our modeling approach for light-driven metabolism exemplifies how integration of largely unvisited data types, such as physicochemical environmental parameters, can expand the diversity of applications of metabolic networks.
Metabolic network reconstruction encompasses existing knowledge about an organism's metabolism and genome annotation, providing a platform for omics data analysis and phenotype prediction. The model alga Chlamydomonas reinhardtii is employed to study diverse biological processes from photosynthesis to phototaxis. Recent heightened interest in this species results from an international movement to develop algal biofuels. Integrating biological and optical data, we reconstructed a genome-scale metabolic network for this alga and devised a novel light-modeling approach that enables quantitative growth prediction for a given light source, resolving wavelength and photon flux. We experimentally verified transcripts accounted for in the network and physiologically validated model function through simulation and generation of new experimental growth data, providing high confidence in network contents and predictive applications. The network offers insight into algal metabolism and potential for genetic engineering and efficient light source design, a pioneering resource for studying light-driven metabolism and quantitative systems biology.
PMCID: PMC3202792 PMID: 21811229
Chlamydomonas reinhardtii; lipid metabolism; metabolic engineering; photobioreactor
19. Exon definition as a potential negative force against intron losses in evolution
Biology Direct 2008;3:46.
Previous studies have indicated that the wide variation in intron density (the number of introns per gene) among different eukaryotes largely reflects varying degrees of intron loss during evolution. The most popular model, which suggests that organisms lose introns through a mechanism in which reverse-transcribed cDNA recombines with the genomic DNA, concerns only one mutational force.
Using exons as the units of splicing-site recognition, exon definition constrains the length of exons. An intron-loss event results in fusion of flanking exons and thus a larger exon. The large size of the newborn exon may cause splicing errors, i.e., exon skipping, if the splicing of pre-mRNAs is initiated by exon definition. By contrast, if the splicing of pre-mRNAs is initiated by intron definition, intron loss does not matter. Exon definition may thus be a selective force against intron loss. An organism with a high frequency of exon definition is expected to experience a low rate of intron loss throughout evolution and have a high density of spliceosomal introns.
The majority of spliceosomal introns in vertebrates may be maintained during evolution not because of potential functions, but because of their splicing mechanism (i.e., exon definition). Further research is required to determine whether exon definition is a negative force in maintaining the high intron density of vertebrates.
This article was reviewed by Dr. Scott W. Roy (nominated by Dr. John Logsdon), Dr. Eugene V. Koonin, and Dr. Igor B. Rogozin (nominated by Dr. Mikhail Gelfand). For the full reviews, please go to the Reviewers' comments section.
PMCID: PMC2614967 PMID: 19014515
20. Mechanisms Used for Genomic Proliferation by Thermophilic Group II Introns
PLoS Biology 2010;8(6):e1000391.
Studies of mobile group II introns from a thermophilic cyanobacterium reveal how these introns proliferate within genomes and might explain the origin of introns and retroelements in higher organisms.
Mobile group II introns, which are found in bacterial and organellar genomes, are site-specific retroelments hypothesized to be evolutionary ancestors of spliceosomal introns and retrotransposons in higher organisms. Most bacteria, however, contain no more than one or a few group II introns, making it unclear how introns could have proliferated to higher copy numbers in eukaryotic genomes. An exception is the thermophilic cyanobacterium Thermosynechococcus elongatus, which contains 28 closely related copies of a group II intron, constituting ∼1.3% of the genome. Here, by using a combination of bioinformatics and mobility assays at different temperatures, we identified mechanisms that contribute to the proliferation of T. elongatus group II introns. These mechanisms include divergence of DNA target specificity to avoid target site saturation; adaptation of some intron-encoded reverse transcriptases to splice and mobilize multiple degenerate introns that do not encode reverse transcriptases, leading to a common splicing apparatus; and preferential insertion within other mobile introns or insertion elements, which provide new unoccupied sites in expanding non-essential DNA regions. Additionally, unlike mesophilic group II introns, the thermophilic T. elongatus introns rely on elevated temperatures to help promote DNA strand separation, enabling access to a larger number of DNA target sites by base pairing of the intron RNA, with minimal constraint from the reverse transcriptase. Our results provide insight into group II intron proliferation mechanisms and show that higher temperatures, which are thought to have prevailed on Earth during the emergence of eukaryotes, favor intron proliferation by increasing the accessibility of DNA target sites. We also identify actively mobile thermophilic introns, which may be useful for structural studies, gene targeting in thermophiles, and as a source of thermostable reverse transcriptases.
Author Summary
Group II introns are bacterial mobile elements thought to be ancestors of introns and retroelements in higher organisms. They comprise a catalytically active intron RNA and an intron-encoded reverse transcriptase, which promotes splicing of the intron from precursor RNA and integration of the excised intron into new genomic sites. While most bacteria have small numbers of group II introns, in the thermophilic cyanobacterium Thermosynechococcus elongatus, a single intron has proliferated and constitutes 1.3% of the genome. Here, we investigated how the T. elongatus introns proliferated to such high copy numbers. We found divergence of DNA target specificity, evolution of reverse transcriptases that splice and mobilize multiple degenerate introns, and preferential insertion into other mobile introns or insertion elements, which provide new integration sites in non-essential regions of the genome. Further, unlike mesophilic group II introns, the thermophilic T. elongatus introns rely on higher temperatures to help promote DNA strand separation, facilitating access to DNA target sites. We speculate how these mechanisms, including elevated temperature, might have contributed to intron proliferation in early eukaryotes. We also identify actively mobile thermophilic introns, which may be useful for structural studies and biotechnological applications.
PMCID: PMC2882425 PMID: 20543989
21. Evolutionary dynamics of U12-type spliceosomal introns
Many multicellular eukaryotes have two types of spliceosomes for the removal of introns from messenger RNA precursors. The major (U2) spliceosome processes the vast majority of introns, referred to as U2-type introns, while the minor (U12) spliceosome removes a small fraction (less than 0.5%) of introns, referred to as U12-type introns. U12-type introns have distinct sequence elements and usually occur together in genes with U2-type introns. A phylogenetic distribution of U12-type introns shows that the minor splicing pathway appeared very early in eukaryotic evolution and has been lost repeatedly.
We have investigated the evolution of U12-type introns among eighteen metazoan genomes by analyzing orthologous U12-type intron clusters. Examination of gain, loss, and type switching shows that intron type is remarkably conserved among vertebrates. Among 180 intron clusters, only eight show intron loss in any vertebrate species and only five show conversion between the U12 and the U2-type. Although there are only nineteen U12-type introns in Drosophila melanogaster, we found one case of U2 to U12-type conversion, apparently mediated by the activation of cryptic U12 splice sites early in the dipteran lineage. Overall, loss of U12-type introns is more common than conversion to U2-type and the U12 to U2 conversion occurs more frequently among introns of the GT-AG subtype than among introns of the AT-AC subtype. We also found support for natural U12-type introns with non-canonical terminal dinucleotides (CT-AC, GG-AG, and GA-AG) that have not been previously reported.
Although complete loss of the U12-type spliceosome has occurred repeatedly, U12 introns are extremely stable in some taxa, including eutheria. Loss of U12 introns or the genes containing them is more common than conversion to the U2-type. The degeneracy of U12-type terminal dinucleotides among natural U12-type introns is higher than previously thought.
PMCID: PMC2831892 PMID: 20163699
22. Comparative analysis of information contents relevant to recognition of introns in many species
BMC Genomics 2011;12:45.
The basic process of RNA splicing is conserved among eukaryotic species. Three signals (5' and 3' splice sites and branch site) are commonly used to directly conduct splicing, while other features are also related to the recognition of an intron. Although there is experimental evidence pointing to the significant species specificities in the features of intron recognition, a quantitative evaluation of the divergence of these features among a wide variety of eukaryotes has yet to be conducted.
To better understand the splicing process from the viewpoints of evolution and information theory, we collected introns from 61 diverse species of eukaryotes and analyzed the properties of the nucleotide sequences relevant to splicing. We found that trees individually constructed from the five features (the three signals, intron length, and nucleotide composition within an intron) roughly reflect the phylogenetic relationships among the species but sometimes extensively deviate from the species classification. The degree of topological deviation of each feature tree from the reference trees indicates the lowest discordance for the 5' splicing signal, followed by that for the 3' splicing signal, and a considerably greater discordance for the other three features. We also estimated the relative contributions of the five features to short intron recognition in each species. Again, moderate correlation was observed between the similarities in pattern of short intron recognition and the genealogical relationships among the species. When mammalian introns were categorized into three subtypes according to their terminal dinucleotide sequences, each subtype segregated into a nearly monophyletic group, regardless of the host species, with respect to the 5' and 3' splicing signals. It was also found that GC-AG introns are extraordinarily abundant in some species with high genomic G + C contents, and that the U12-type spliceosome might make a greater contribution than currently estimated in most species.
Overall, the present study indicates that both splicing signals themselves and their relative contributions to short intron recognition are rather susceptible to evolutionary changes, while some poorly characterized properties seem to be preserved within the mammalian intron subtypes. Our findings may afford additional clues to understanding of evolution of splicing mechanisms.
PMCID: PMC3033335 PMID: 21247441
23. Explaining evolution via constrained persistent perfect phylogeny
BMC Genomics 2014;15(Suppl 6):S10.
The perfect phylogeny is an often used model in phylogenetics since it provides an efficient basic procedure for representing the evolution of genomic binary characters in several frameworks, such as for example in haplotype inference. The model, which is conceptually the simplest, is based on the infinite sites assumption, that is no character can mutate more than once in the whole tree. A main open problem regarding the model is finding generalizations that retain the computational tractability of the original model but are more flexible in modeling biological data when the infinite site assumption is violated because of e.g. back mutations. A special case of back mutations that has been considered in the study of the evolution of protein domains (where a domain is acquired and then lost) is persistency, that is the fact that a character is allowed to return back to the ancestral state. In this model characters can be gained and lost at most once. In this paper we consider the computational problem of explaining binary data by the Persistent Perfect Phylogeny model (referred as PPP) and for this purpose we investigate the problem of reconstructing an evolution where some constraints are imposed on the paths of the tree.
We define a natural generalization of the PPP problem obtained by requiring that for some pairs (character, species), neither the species nor any of its ancestors can have the character. In other words, some characters cannot be persistent for some species. This new problem is called Constrained PPP (CPPP). Based on a graph formulation of the CPPP problem, we are able to provide a polynomial time solution for the CPPP problem for matrices whose conflict graph has no edges. Using this result, we develop a parameterized algorithm for solving the CPPP problem where the parameter is the number of characters.
A preliminary experimental analysis shows that the constrained persistent perfect phylogeny model allows to explain efficiently data that do not conform with the classical perfect phylogeny model.
PMCID: PMC4240218 PMID: 25572381
perfect phylogeny; persistent perfect phylogeny; fixed-parameter complexity
24. Using Likelihood-Free Inference to Compare Evolutionary Dynamics of the Protein Networks of H. pylori and P. falciparum
PLoS Computational Biology 2007;3(11):e230.
Gene duplication with subsequent interaction divergence is one of the primary driving forces in the evolution of genetic systems. Yet little is known about the precise mechanisms and the role of duplication divergence in the evolution of protein networks from the prokaryote and eukaryote domains. We developed a novel, model-based approach for Bayesian inference on biological network data that centres on approximate Bayesian computation, or likelihood-free inference. Instead of computing the intractable likelihood of the protein network topology, our method summarizes key features of the network and, based on these, uses a MCMC algorithm to approximate the posterior distribution of the model parameters. This allowed us to reliably fit a flexible mixture model that captures hallmarks of evolution by gene duplication and subfunctionalization to protein interaction network data of Helicobacter pylori and Plasmodium falciparum. The 80% credible intervals for the duplication–divergence component are [0.64, 0.98] for H. pylori and [0.87, 0.99] for P. falciparum. The remaining parameter estimates are not inconsistent with sequence data. An extensive sensitivity analysis showed that incompleteness of PIN data does not largely affect the analysis of models of protein network evolution, and that the degree sequence alone barely captures the evolutionary footprints of protein networks relative to other statistics. Our likelihood-free inference approach enables a fully Bayesian analysis of a complex and highly stochastic system that is otherwise intractable at present. Modelling the evolutionary history of PIN data, it transpires that only the simultaneous analysis of several global aspects of protein networks enables credible and consistent inference to be made from available datasets. Our results indicate that gene duplication has played a larger part in the network evolution of the eukaryote than in the prokaryote, and suggests that single gene duplications with immediate divergence alone may explain more than 60% of biological network data in both domains.
Author Summary
The importance of gene duplication to biological evolution has been recognized since the 1930s. For more than a decade, substantial evidence has been collected from genomic sequence data in order to elucidate the importance and the mechanisms of gene duplication; however, most biological characteristics arise from complex interactions between the cell's numerous constituents. Recently, preliminary descriptions of the protein interaction networks have become available for species of different domains. Adapting novel techniques in stochastic simulation, the authors demonstrate that evolutionary inferences can be drawn from large-scale, incomplete network data by fitting a stochastic model of network growth that captures hallmarks of evolution by duplication and divergence. They have also analyzed the effect of summarizing protein networks in different ways, and show that a reliable and consistent analysis requires many aspects of network data to be considered jointly; in contrast to what is commonly done in practice. Their results indicate that duplication and divergence has played a larger role in the network evolution of the eukaryote P. falciparum than in the prokaryote H. pylori, and emphasize at least for the eukaryote the potential importance of subfunctionalization in network evolution.
PMCID: PMC2098858 PMID: 18052538
25. Rapid Pathway Evolution Facilitated by Horizontal Gene Transfers across Prokaryotic Lineages
PLoS Genetics 2009;5(3):e1000402.
The evolutionary history of biological pathways is of general interest, especially in this post-genomic era, because it may provide clues for understanding how complex systems encoded on genomes have been organized. To explain how pathways can evolve de novo, some noteworthy models have been proposed. However, direct reconstruction of pathway evolutionary history both on a genomic scale and at the depth of the tree of life has suffered from artificial effects in estimating the gene content of ancestral species. Recently, we developed an algorithm that effectively reconstructs gene-content evolution without these artificial effects, and we applied it to this problem. The carefully reconstructed history, which was based on the metabolic pathways of 160 prokaryotic species, confirmed that pathways have grown beyond the random acquisition of individual genes. Pathway acquisition took place quickly, probably eliminating the difficulty in holding genes during the course of the pathway evolution. This rapid evolution was due to massive horizontal gene transfers as gene groups, some of which were possibly operon transfers, which would convey existing pathways but not be able to generate novel pathways. To this end, we analyzed how these pathways originally appeared and found that the original acquisition of pathways occurred more contemporaneously than expected across different phylogenetic clades. As a possible model to explain this observation, we propose that novel pathway evolution may be facilitated by bidirectional horizontal gene transfers in prokaryotic communities. Such a model would complement existing pathway evolution models.
Author Summary
Many biological functions, from energy metabolism to antibiotic resistance, are carried out by biological pathways that require a number of cooperatively functioning genes. Hence, underlying mechanisms in the evolution of biological pathways are of particular interest. However, compared to the evolution of individual genes, which has been well studied, the evolution of biological pathways is far less understood. In this study, we used the abundant genome sequences available today and a novel algorithm we recently developed to trace the evolutionary history of prokaryotic metabolic pathways and to analyze how these pathways emerged. We found that the pathways have experienced significantly rapid acquisition, which would play a key role in eliminating the difficulty in holding genes during the course of pathway evolution. In addition, the emergence of novel pathways was suggested to have occurred more contemporaneously than expected across different phylogenetic clades. Based on these observations, we propose that novel pathway evolution can be facilitated by bidirectional horizontal gene transfers in prokaryotic communities. This simple model may approach the question of how biological pathways requiring a number of cooperatively functioning genes can be obtained and are the core event within the evolution of biological pathways in prokaryotes.
PMCID: PMC2644373 PMID: 19266023
Results 1-25 (1022161)
|
__label__1
| 0.659158
|
Generalized Functions
The Wolfram Language's symbolic character allows it to handle generalized functions or "distributions" as a direct extension of classical mathematical functions, and to represent integrals and integral transforms that cannot be expressed in terms of continuous functions.
DiracDelta one-dimensional or multidimensional delta function
HeavisideTheta Heaviside step function, for and for
DiracComb ▪ HeavisidePi ▪ HeavisideLambda
Integrate, D integrals and derivatives of generalized functions
LaplaceTransform, FourierTransform integral transforms
Convolve convolve generalized functions
FunctionExpand expand out generalized functions
Translate this page:
|
__label__1
| 0.919082
|
Diets in Review - Find the Right Diet for You
Swim for an Effective Total Body Workout
woman swimmingSwimming is one of the best total body workouts for your body. Swimming, unlike running (for most people), is easy on the joints and can be fun depending on the type of swimming you are doing. Swimming with friends is a great way to enjoy yourself as well as enhance your physical and mental strength and endurance. This is also a great way to change up your workouts from time-to-time.
Research has shown that swimming workouts burn approximately three calories a mile per pound of body weight. One mile is 1,609 meters. So for a 150 pound person, at a 30-minute/mile pace, they would burn around 900 calories. Nine hundred calories in a half hour; it takes an hour on the treadmill at a fast pace to burn 900 calories! Below are a few different swimming workouts that you may want to give a shot!
Swim Workout 1:
Try each stroke for 25 meters: Front Crawl, Breast Stroke, Butterfly, Elementary Back Stroke, Back Crawl, and Side Stroke.
Swim Workout 2:
Try each of the previous strokes for 50 meters.
Swim Workout 3:
Try each previous stroke for 25 meters then tread water for 10 minutes and repeat.
Swim Workout 4:
Tread water for three minutes before performing each stroke for 50 meters. Example: Tread then breast stroke for 50 meters, then tread again before going into the front crawl and so on.
Swim Workout 5: Swim for as long as you can without stopping any stroke, plus the dog paddle. If you can only swim for a few minutes at a time, it is alright, just try and increase your swim time next time.
Here are a few stretches you should try before swimming:
March 8th, 2009
|
__label__1
| 0.83789
|
Welcome! You are browsing as a guest
yarns > Fiddle Knits > Etude Lace
Etude Lace
Fiddle Knits
Lace / 2 ply ?
875 yards (800 meters)
100 grams (3.53 ounces)
80% Merino
20% Silk
Etude Lace is an 80/20 blend of merino wool and silk. It’s soft and has a subtle sheen to it from the silk content.
TECHNICAL INFO: This yarn is dyed using acid dyes. Yarn was washed using unscented wool wash after dying. Please be aware that hand dyed yarns might bleed color slightly during their first washing.
popular colorways
3 stashed
4 projects
6 stashed
3 projects
4 stashed
8 projects
Morning Clouds
1 stashed
9 projects
3 stashed
4 projects
3 stashed
7 projects
|
__label__1
| 0.641961
|
Top 10 Tallest Active NBA Players
It’s not news that basketball players tend to be on the tall side. But did you know that the average height of an NBA player is 6 feet 7 inches? When your career depends on your ability to take lengthy strides and reach 10-foot-high baskets, it’s not very surprising that the taller a basketball player, the better suited they are for the game.
Although there have been some short players in the NBA over the years, the vast majority of players tend to be giants (at least by non-NBA standards). Being tall is an advantage to both offensive as well as defensive players. From delivering the perfect slam dunk or 3-pointer, to preventing someone else from doing so, a player’s height plays a crucial role at every stage in the game. Since the goal of basketball is to deliver the ball to such a high basket, the advantages of being tall are pretty obvious. So, players who reach staggering heights (pun intended) in the sport are usually those who are taller than their opponents.
However, height is not the only factor that determines a player’s success in the game. The tallest players may not necessarily be the most speedy or agile. Many tall players may be clumsy because of the added coordination it requires for them to move around the court. Generally speaking, the highest-paid players are those who have a perfect combo of height and agility. Of course, being associated with a successful team helps as well. Here we list out the 10 tallest active NBA superstars and see how their salaries measure up.
10. Andrea Bargnani – 7’0″ – $10.75 million in 2013-14
Currently wearing jersey number 7 in the New York Knicks, Andrea Bargnani is originally from Italy. Standing 7’0″ tall and weighing in at 256 pounds, Bragnani began his basketball career in 2006. Before joining the Knicks squad, he played for the Toronto Raptors from 2006 to 2013. Nicknamed “Il Mago”, or “The Magician”, he helped the Raptors reach the Playoffs in his first two seasons with the team. Bargnani played in the Italian Serie A and the Euroleague prior to joining the NBA. As a forward for the Knicks, the 27-year-old athlete is making $10.75 million this season.
|
__label__1
| 0.999992
|
Here's a new entry into the continuing discussion on the Black and Latino experience.
NEGRITA, a forthcoming documentary from director/producer Magdalena Albizu, will look deeper into the experience of Afro Latinas in the United States. Consider this akin to the Black and Latino mini-doc that emerged back in January. But unlike that 10-minute piece, this project looks to be a feature-length doc with a scholarly focus on women.
The summary:
"NEGRITA will expose the dynamics of being 'Black,' the current tone of race relations between African-Americans and Hispanics in the United States, and how the Latino perception of being ‘Black’ affects Afro Latinas in the country, regardless of culture and nationality.
Why are Afro Latinas encouraged to 'marry lighter' in order to adelantar la raza (advance the race)? Why do Latinos tend to define and favor their Spanish and Indigenous heritage and often choose to identify as anything but Black?"
The production team includes producer Ingrid Matias, director of photography Donavan Lambert, and videograper Eddie Bailey.
The filmmakers are seeking $20,000 to cover the costs of research, equipment, transportation and crew, and have 15 days left to do so. Find their pitch below, and if you like what you see, click HERE to contribute.
|
__label__1
| 0.989437
|
ingredient information
Glycerol Monooleate
Friction modifiers are added to lubricants to reduce the surface friction of the lubricated parts. Typically these are polar chemical compounds having high affinity for metal surfaces and possessing long alkyl chains. Glycerol mono-oleate is a common example of a friction modifier. This additive is needed in limited slip differentials. Glycerol is an organic compound, also commonly called glycerin or glycerine. It is a colorless, odorless, viscous liquid that is widely used in pharmaceutical formulations. Glycerol has three hydrophilic hydroxyl groups that are responsible for its solubility in water and its hygroscopic nature. The glycerol substructure is a central component of many lipids. Glycerol is sweet-tasting and of low toxicity. In foods and beverages, glycerol serves as a humectant, solvent and sweetener, and may help preserve foods. It is also used as filler in commercially prepared low-fat foods (e.g., cookies), and as a thickening agent in liqueurs. Glycerol and water are used to preserve certain types of leaves. As a sugar substitute, it has approximately 27 calories per teaspoon and is 60 percent as sweet as sucrose. Although it has about the same food energy as table sugar, it does not raise blood sugar levels, nor does it feed the bacteria that form plaques and cause dental cavities. As a food additive, glycerol is labeled as E number E422. Glycerol is also used to manufacture mono- and di-glycerides for use as emulsifiers, as well as polyglycerol esters going into shortenings and margarine. It is also used as a humectant (along with propylene glycol labelled as E1520 and/or E422) in the production of snus, a Swedish style snuff that the Swedish government subjects to the same regulations as "food" because it is used orally.
|
__label__1
| 0.580056
|
User login
They Wait
Review by:
Release Date:
Aspect Ratio:
Directed by:
Ernie Barbarash
Jaime King
Terry Chen
Pei-pei Cheng
Michael Biehn
Bottom Line:
Click to Play
Sarah and Jason are a happy couple, living in Shanghai and raising their son Sammy. Jason is a hard worker, dedicated to the opening of his company’s newest office. Sarah (King) is a loving mother. Sammy is a typical kid with a rampant imagination and trouble sleeping in his own bed.
Jason receives a phone call in the middle of the night, informing him of his uncle’s death. Soon, the trio travel to the funeral during the festival known as Ghost Month. Sammy (Chen) almost stumbles into the forbidden part of the house, but he is stopped by Jason’s last living uncle. That scare is enough for him, and Sarah takes Sammy out of the house for some fresh air.
After running into an old photographer friend, Blake (Terminator and Aliens’ Michael Biehn), Sarah finds a pharmacist, and Sammy finds more information on the demons he sees. Soon, Sammy comes face to face with his first demon, and a possible mentor in the strange pharmacist (Henry O). Sammy has a gift no one wants – the ability to see the dead as they come to accept the sacrifices offered them during the festival. Sammy gets his gift from his mother and she soon begins seeing her own troubled visions.
Sammy soon encounters an inviting ghost who leads him back to the forbidden area. This lab houses the processing facility where the deceased uncles employed their workers. The Chinese Humanitarian Society would often process corpses and return the bones back to their homeland. In this place, under frightening conditions, Sammy undergoes a change, setting forth the moments that will define his life, his mother and the relationship they share.
King has developed into a well-rounded actress, showing more acting chops than legs in this creepy flick. Chen is great as the focal point of the film’s first act, shifting from careful curiosity to outright panic as the script demands.
They Wait will inevitably be compared to other Asian horror films and while there are similarities, any connection should be limited to genre alone. Ghosts and children have been at the heart of horror for decades, and while They Wait bears similarities to films like The Eye, it can just as easily be compared to Poltergeist. King’s need to track down the truth between worlds mirrors films like The Ring and The Grudge, but the film’s creativity arms it with a solid chance to overcome the retread of popular premises. Sarah’s willingness to sacrifice for her son’s life provides the payoff pitch. Justice for those who deserve it is the key to whether or not viewers rank They Wait as its own film and not a re-tread hinges on this climax.
Hal Beckett’s original music accentuates the jumps and jolts of the film. The music is beautifully supportive of the film’s peace, making shocks stand out even more.
Your rating: None
|
__label__1
| 0.605626
|
Organized Labour, Govt Agree To Meet On Jan 26 Over Utility Hikes
The government and organised labour have made some progress towards reaching a common ground in their negotiations on workers’ demands over the upward adjustments in petroleum prices and utility tariffs.
The Minister of Employment and Labour Relations, Mr Haruna Idrissu, explained that that was after the government had agreed to provide a lifeline for the vulnerable, while organised labour also adjusted its earlier positions.
At a crunch meeting at the Flagstaff House yesterday, both parties agreed to meet on January 26 to bring finality to the negotiations to ensure industrial peace and harmony.
“I am happy to announce that we have made some progress and I am hopeful that in the early part of next week we will be able to reach a consensus with organised labour,” Mr Idrissu said.
The Secretary-General of the Trades Union Congress (TUC), Mr Kofi Asamoah, said the leadership would carry out further consultations with their members on the proposals put forward by the government.
Earlier in his opening remarks, the Employment Minister had said he had forwarded the demands made by organised labour to the President.
However, he made it clear that current economic conditions made it difficult for the government to meet those demands.
Finance Minister
The Finance Minister, Mr Seth Terkper, who was at the meeting, took the labour leaders through the prevailing economic position of the country.
He explained to them the need for the introduction of the tariffs to instill sanity in the economy and also address the power crisis.
Thousands of Ghanaian workers across the country last Wednesday poured onto the streets to demonstrate against the recent hikes in fuel and utility prices.
They wanted the government to withdraw the recently introduced Energy Sector Levies Act, which has led to a 28 per cent increase in the prices of petroleum products.
Besides, the workers wanted water and electricity tariffs, which have witnessed over 50 per cent increases, to be reduced drastically.
Two earlier meetings held between the government negotiating team and organised labour ended in deadlock, leading to the demonstration.
Labour threatened to follow a road map that would lead to a strike.
However, after yesterday’s meeting, Mr Asamoah said they would hold their fire until next week when they hoped to put an end to the disagreement.
However, he told journalists: “We will cross the bridge when nothing positive comes out of the final meeting.”
Source: Daily Graphic
|
__label__1
| 0.925813
|
12x12 frame
LeNae Gerig
12x12 frame
By LeNae Gerig
Click to Enlarge
Designer's Tip: Use wood, paper and metal elements on this collaged 3-D frame. Add some color and bring out the pattern in the paper leaves by blotting with the surface of an inkpad.
1. Fold the bottom corner of the tan handwriting paper forward by 2". Glue a square of red dot paper behind the folded piece and glue to the center of the black frame.
2. Mat a 5"x7" photo with textured red paper, leaving a 1/8" border, and brown cardstock, leaving a 1/2" border. Glue to the left side of the frame with the bottom corner under the fold. Glue the fold in place.
3. Write on the journaling note card and tuck under the right side of the brown mat. Glue the postcard in place. Glue another journaling note under the top right corner of the photo.
4. Adhere the swirl to the left side of the photo and glue tiny paper flowers and wood heart buttons threaded with red twine to the swirl.
5. Blot the paper leaves with the brown inkpad to color. Glue under the flowers on the fold at the journaling note. Thread flower buttons with yellow twine and glue to the red dot paper under the fold. Glue 2 large buttons the post cards.
6. Cover a chipboard door with red textured paper and trim around the door using the penknife. Lightly sand the edges and glue to the bottom right corner of the frame.
7. Foam tape a wood tag to the top left side of the photo mat and the wood flags on the right corner of the mat. Foam tape a black blank ticket to overlap the chipboard door. Glue a twine threaded heart button to the blank ticket.
8. Glue password notes below the photo and inside the chipboard door.
|
__label__1
| 0.676534
|
Rappaccini’s Daughter Summary Part 2
Rappaccini’s Daughter Summary Part 2
Table of Contents
Summary Part 2
Summary Part 3
Baglioni also tells him that Doctor Rappaccini is fascinated with vegetable and natural poisons and although the narrator states that there is a professional rivalry between Baglioni and Rappaccini, Giovanni wonders that at least Rappaccini must feel for his own daughter. Baglioni says he does not and that she herself (Beatrice) is an object of curiosity, both because of her beauty and high state of education from her father. Giovanni, still taking this in, leaves and with Beatrice in his mind, buys a bouquet of flowers to take back to his lodgings.
He returns with is flowers and sits, admiring the garden at his window before suddenly seeing Beatrice come out, looking radiant and he thinks again of the “analogy between the beautiful girl and the gorgeous shrub” that is in the middle of the strange garden. He watches as she approaches the strange purple flower bush and hears as she calls it “sister” as she tends to it. He also spots a small lizard that approaches Beatrice and a bit of moisture from the flower falls upon it and the lizard convulses and dies. He wonders if his imagination is betraying him and as he does so, he sees an insect that comes toward Beatrice as if attracted to her but upon coming near her, it too suddenly dies. Without knowing what he is doing, Giovanni suddenly throws the bouquet of flowers down to her in a greeting, asking her to wear one of the flowers but as she leaves and the bouquet remains, it begins to wilt and die almost immediately.
For the next several days, Giovanni tries to avoid the window and realizes that if he were wise, he would leave the lodgings, especially since his toss of the flowers opened a line of communication between the two. He is nonetheless unable to think of anything but Beatrice and one afternoon encounters Baglioni again on the streets and as Giovanni tries to avoid a conversation, the infamous dark Doctor Rappaccini comes along the sidewalk toward them and he gives Giovanni a strange cold glance. Baglioni insists that he must have scientific plans for him but Giovanni leaves him there, wondering what to do next and somehow understands that Rappaccini’s daughter is the cause for Giovanni’s distracted state.
As Giovanni returns home, his servant, Dame Lisabetta, shows him a secret entrance to the garden. He wanders in, not caring if Beatrice is an “angel or a demon” and admires the strange plants before happening upon Beatrice. He is completely taken with her and although he hints at what odd sights he saw, he does not address them directly and instead the two engage in flirtation. As they talk, Beatrice suddenly remembers to tend to the purple flower. They move near it but as Giovanni goes to touch it, she stops him, telling him it is fatal. He backs away and suddenly notices that Doctor Rappaccini is watching them but he doesn’t know for how long it had been. He returns to his chambers and is unable to think of anything but Rappaccini’s daughter.
|
__label__1
| 0.633659
|
Writer’s Block: Thoughts from a coaching seminar
Two weeks ago I wrote about the Minnesota State High School League’s “Why We Play” program and a coaches seminar at Coon Rapids High School.
Jason Olson
Jason Olson
I’ve never coached an organized team from the start of a season, so I haven’t had the chance to experience the roller coaster of emotions that make up a full season. I have helped run soccer practices here and there in my free time away from my newspaper duties. The practices were mostly fun, side games or introducing a new idea like how to defend a corner kick or more technical stuff, but it revolved around youth soccer programs in their infancy.
I have more experience with watching coaches from afar at games or practices. The variety of approaches is massive, but all seemed to have the students interests ahead of their own.
I learned several things from the condensed seminar at Coon Rapids, but what I’ve learned the most during my time working with more than a few of these educators is how much they genuinely care about the kids.
Of course we all would like to see a state title from every team, every season. That might be a goal but beyond that, what is the purpose of sport?
Teams are always going to prepare and perform to win each time they compete. That isn’t a purpose. Like Minnesota State High School League Associate Director Jody Redman described:“It’s two things. Human growth and development of the kids and connecting them to their school [and greater community].”
Separation of that goal (winning) from purpose (learn lifelong skills like teamwork, accountability and the other positive traits we look for in society) was one of the more poignant takeaways for me.
Looking back, common sense should say that in an educational-based athletic program (schools versus club-level team) the purpose should be more thoughtful than the famous Vince Lombardi quote of “Winning isn’t everything. It is the only thing.”
It sounds good in a quip or something to motivate a group of football players in a locker room before kickoff on a crisp fall night to get the emotions going. But we need to dig deeper than that.
The program looked at Joe Ehrmann’s book, “Inside Out Coaching” where he helps coaches develop a coaches statement and in turn develop that purpose using four questions: Why I coach? Why I coach the way I do? How does it feel to be coached by me? How do I define and measure success?
I received an email from a frustrated parent who appreciated the original piece but offered another angle. Paraphrasing their question: what happens when the coach puts winning as a purpose instead of a goal?
I think feelings are always going to be strong when a student is cut from a program or isn’t used in what they believe to be the best way to win.
I know the horrible feeling of being cut, but it helped form what I guess would be considered a purpose looking back as motivation to try a new sport.
Those that don’t make a team might have strong thoughts about winning at all costs, no matter age or experience level.
This begs the larger question to be answered about a play-up policy where upperclassmen are given priority on a varsity-level team over an underclassman.
I’ve seen compelling arguments on both sides of the issue from the senior that played on the JV team for three years and missed out on the varsity team for a younger student with more talent to the eighth-grader that excels on a national stage not be able to possibly bring a state title to the local school because of their age.
I’m not sure I have the perfect answer for this but I’m going to try and give my thoughts.
I understand the argument for high school varsity teams being reserved for juniors and seniors only. It is a scholastic-first idea and therefore, should be reserved as a reward for those that played at the younger levels in the program.
On the other side, if a goal is to win, shouldn’t coaches be able to start or dress those students they believe give the team the best chance to win regardless of age?
As long as the goals and purpose are clear and shared with administrators, parents and students, I believe the current state standard in place of seventh grade or older is a fitting guideline and should remain in place.
While the experience of playing a varsity sport is a unique life experience, that shouldn’t stand in the way of a capable younger student taking a spot simply based on age. That seems discriminatory on the basis of age and in all reality entitlement. Whomever performs better on the field, rink, mat or pool should earn that spot to help the team instead of giving one student a few more high school memories.
I know this might be harsh, but it seems like the only logical solution, coming from a senior captain who was a last-man cut as a freshman.
Jason Olson can be reached at [email protected]
|
__label__1
| 0.738351
|
Pundit Interviews
Pundit Letters
Perishable Pundit
P.O. Box 810425
Boca Raton FL 33481
Ph: 561-994-1118
Fax: 561-994-1610
Produce Business
Deli Business
American Food & Ag Exporter
Cheese Connoisseur
Jim Prevor’s Perishable Pundit, November 5, 2012
The New York Produce Show and Conference is an unusual event. More intimate than the larger shows, it is second to none in its ambition to provide a world-class event in the Capital of the World.
With this year, we have expanded our University Exchange Program across the Atlantic to a most extraordinary Italian University, and the Professor the school is sending over is doing extraordinarily interesting research. We asked Pundit Investigator and Special Projects Editor Mira Slott to find out more:
Gabriella Morini
Assistant Professor
(Ricercatore — Researcher)
Taste and Food Sciences
University of Gastronomic Sciences
(Universita Degli Studi Di Scienze Gastronomiche)
Pollenzo, Italy
Q: Could you provide a preview of your talk? What are the key issues you will bring to light?
A: I will discuss the function of the sense of taste; the influence of taste in food preferences and food choices and therefore on nutrition and health. My research makes the case that vegetables are the best trainers or the optimum way to educate your sense of taste. It is critical to introduce vegetables in the diet as early as possible, not only in children but even during a mother’s pregnancy, to influence and condition taste receptors in order to establish good eating habits and good health that will last in the long term.
Q: Is there a scientific reason why people’s taste buds wouldn’t naturally gravitate toward vegetables? Why is it so challenging to increase produce consumption?
A: I have been working since 1988 on taste sensors -- how sense works with the molecules that are present in the food we eat. I have a paper I wrote in English on the molecular aspects of taste, which might be of interest to your readers. When our ancestors were living in the bush, the only way to decide if we should eat something was to taste it. There were no labels.
People were learning in no uncertain terms what was poisonous and what was not. We never think about the chemical composition we eat in terms of taste. Everyone likes foods that are sweet or salted, and fat taste lipids are important. We also have receptors for umami, a Japanese word meaning a pleasant savory taste. This is what we naturally prefer.
We don’t like much bitter taste. Think about a baby or child and what they do when we put something bitter on their plate. We also don’t like acidic foods. It might be spoiled because it has undergone fermentation. Most of the bitter compounds are coming from plants. Plants protect themselves from being eaten from animals.
Q: Doesn’t our sense of taste mature over our lifetime? For example, adults often prefer more bitter tastes than children. Is this based on biological or environmental factors? What about food preferences built on cultural and religious differences and rituals, etc.?
A: When we grow up, we change our sense of taste, especially regarding bitter. Adults like beer, coffee, and many other things bitter. There are also differences within cultures. For example, in Italy, we have a word amaro, collectively used for bitter liqueurs, which are considered medicinal and served at the end of a meal to aid digestion.
On one side, there are information-built receptors and genetics, but also humans are different than other animals. Humans are not as strict on what we eat. It’s not just receptors, but the culture and other causes. There are people who eat cows and those who don’t, people who eat dogs and those who don’t, and the same with snakes. Raw meat is important in some parts of the world and not others.
We know that children and also adults don’t eat that many vegetables. They’re bitter and astringent.
Scientists have been working on studies to show that if you get people used to eating vegetables at a young age, it will change their taste preferences. There is also evidence that when a mother eats vegetables during pregnancy and breast feeding, it impacts a gene of taste preference
If we start introducing vegetables to babies, and serve them to toddlers, we will build a taste preference for vegetables. Koalas only eat one thing. Humans adapt to what we have available. In humans, we see we can get used to eating what is healthy.
Q: Has our genetic system and sense of taste evolved to adjust to modernity and the transformations in the food supply chain?
A: Our genetic system is geared to prefer fat and salt. We eat food because we have to. We eat molecules introduced through food to survive. We have senses that influence our food preferences. We do like sweet, salty, umami, and fat because of our genetic system that accommodated a time where there was not too much food.
The problem until 100 years ago was not eating enough. The world has changed. We have a sensory system to detect food that is old. If you go to the grocery store when you are hungry, you buy everything. In the past, there was a long process to get food. Now, we get what we want quickly. It’s important to educate people on this phenomenon. It’s like driving a Ferrari without knowing how; eventually you crash. You need a driver’s license
Q: Using your driving analogy, what are the main lessons people can pull from your research to avoid reckless food choices and reverse unhealthy eating and obesity trends?
A: We need to let people know as much as possible ways to educate sense of taste, to like or to go for healthy. Right now, we need vegetables in our diet more than ever before. Vegetables reduce calorie intake, introduce variety, and are rich in vitamins and antioxidants. We have to improve the consumption of vegetables. One way is to say they are good for you, but that doesn’t always work because we eat what we like. Nobody can force us to eat something we don’t like.
Q: That said, isn’t this an uphill battle to shake conditioned eating behaviors and food preferences?
A: We have to learn to like vegetables. This is the philosophy and there is scientific proof. Researchers have taken groups of children and introduced them to different varieties of vegetables repetitively, leading to a gradual shift in their taste preferences over time, but there is no easy fix.
You bring up eating behaviors. The problem is that it is very difficult to change habits. We are not koalas, so we can learn what to eat and train our genetic system. Now there are scientific papers to show that the best chance for success is to start with children or even better with pregnant mothers.
We also need a multifaceted effort that follows children throughout their daily activities, such as tending a school garden and integrating that into the educational curriculum. In Italy, officials are trying to improve school canteens and include more fresh vegetables.
Children gravitate to peas, carrots and potatoes because they’re not bitter. However, bitter is very good when it comes to vegetables, offering vitamins and nutrients that can’t be found elsewhere. Bitter is better. We have to get people to choose bitter. We have to teach people to like vegetables.
Q: Do you think the produce industry should try to create new vegetable varieties with tastes and flavor profiles that duplicate or simulate what we naturally like?
A: No. We have to retrain our senses to bitter, hot compounds, ginger, onions, chilies, compounds that may have strange tastes… more tastes besides sweet and sour. Also we need a way to recognize these are good for us.
Q: So produce industry executives who look for ways to compete with junk food companies by disguising fruits and vegetables to taste more like the snacks kids desire is not the way to go? For example, produce marketers, and for that matter parents, adding cheese sauce to broccoli, dipping carrots in peanut butter, spreading cream cheese on celery, or drizzling fruit with honey or chocolate could be counter-productive?
A: That is not the right direction. Now we know these bitter vegetable compounds are good for us, and responsible for the taste. It’s a code. We have to learn the language of taste. It’s an investment for a mom to prepare vegetables, but how much time do they invest in getting their children to learn French or German or something else they believe is important.
We have to give the instrument to learn the language of taste, more vegetables and also different ones. I like to say variety is the taste of life. I think it’s not a good approach to reduce bitter taste. There will always be something more fatty, more sweet or salty, or more pleasant out there. The industry will find it difficult to compete if it’s trying to out-sweeten cookies and cake.
Wild animals decide by taste. Humans are different. They may alter food choice depending on which part of the world they live, or which part of the year, say Easter or Christmas. The code is important. We change over our lifetime. We have to try to start at the beginning with what’s good for us. It’s difficult to find people who don’t like cakes.
It is not just about changing the taste code. Competing with junk food is not the solution. I’m reminded of the expression when a food is so good — “to die for” — usually when we eat something very sweet or tasty. If we just continue going that way, we will die… literally.
Broccoli with cheese sauce is just adding calories and avoiding the real issue. It’s a superficial approach.
Q: What tactics do you recommend?
A: The best time to act is when a woman is pregnant. She pays very much attention to her health and will be receptive to information on what she should eat and why it is so important. Lipids, carbohydrates and fats are present in any foods, but there are antioxidants and nutrients in vegetables that are important to human development.
Just as studies show that the music children hear during pregnancy can be influential, research shows that those introduced early to vegetables will gravitate to those tastes. In Italy, there was a concern that when a mother was eating a lot of garlic while breastfeeding, children weren’t eating meat. That’s not the problem now. We need food less rich in easy calories.
Q: There are claims that characteristics of processed foods actually stimulate bad eating habits. Is there truth to that?
A: In the industry, in the 1940s and 1950’s after the Second World War, the only mission was to sell more food. Now we have all the problems with food-related diseases. I think the aim of the industry has changed. I was reading about the ban of big size soda in New York. There is a push to limit calories in meals, reduce portions. In 50 years, we’ve moved from food keeping us alive to the source of what is killing people.
Even in the vegetable world, variety was selected for longer shelf life and the same shape. Minds are changing. What kept us alive can now kill us. At the same time, with so many advances, we live longer.
I’m not one to say the past was better, but our children are the first generation that has less expectancy of life. That is going down hill. The food system, the industry, even fast food, must change. It will be against their business not to change.
Q: As long as there is consumer demand for sweet, salty, fatty and umami, won’t companies continue to produce what is profitable? Despite all the research espousing benefits of produce, and concerted efforts from both government and private organizations to fight obesity, increasing produce consumption remains a challenge. Does the cornerstone of this change require retraining our sense of taste?
A: It’s not easy. It will take time. We don’t have time to adapt genetically. Our body is very much set to adapt to scarcity of food. We are very good at managing scarcity of food, and not good at managing the excess. We cannot wait to adapt biologically, but humans have brains.
Q: With advances in technology, the world has become so mobile, from international travel and exposure to a wide variety of ethnic cuisines, to an array of unusual produce items and unexpected spices. Doesn’t this create heighted interest to experiment with bitter vegetables and daring taste profiles?
A: We know that we have a genetic sense of taste. Detecting receptors of taste is not so different for people living in Ecuador, India, the North Pole or the South Pole. People move around the world and still generally eat the same. Yes, there is ethnic and cultural diversity within communities. I eat a dish that is traditional where I live. It has a sauce made with anchovies and a lot of garlic and raw vegetables. A lot of children in Italy love it. My American friends love peanut butter, but in Europe I don’t know anyone who does. Marmite, a spread from yeast extract, is popular as Vegemite in Australia. I think it’s awful.
But if you think about globalization of food, pizza, pasta, and fast food have become universal because they’re not bitter or acidic at all.
If you have a dog, you know it will eat all the food that is there. As humans, we learn to adapt. Why do we have to use sense of taste when we can go to the supermarket and buy whatever we want? We have to be more aware of what we eat. We can also change when we’re old, but it’s more challenging. If you want to learn an instrument, you’ll learn much faster when you’re a child. It’s the same with sense of taste.
Professor Morini’s research and the presentation that grows out of it is simultaneously perhaps the most inspiring and most challenging presentation we have ever had at The New York Produce Show and Conference.
It is both inspiring and challenging because, though the good Professor may be Italian she reminds us of Aristotle in her approach: She challenges us to be more completely human and identifies rationality as the key trait differentiating humans from animals.
She also touches on a long term concern of ours — what about the vegetables? In pieces such these herehere, here and here, we have cautioned that the produce industry efforts to increase consumption are sometimes uncomfortably close to a bait-and-switch. First, we promote the importance of eating more fruits and vegetables, research which is typically based on a diverse basket of produce items. Then, we run programs that give out only sweet snack fruit which, in and of itself, won’t deliver the promised health benefits.
In our piece titled, The Bitter Truth About Promoting Produce To Children,we examined a study that showed children recoil from the bitter taste of many of the most nutritionally valuable vegetables and analyzed the challenge this posed for efforts to both increase consumption and to use increased consumption to improve public health.
Now Professor Morini comes along with several specific points:
1. The industry is starting too late. It is fine to have school salad bar programs and school snack programs but, we need to start with pregnant women and babies; taste receptors are established in utero.
2. It is not enough to simply increase access to fruits and vegetables. We have to understand that there is a need to consciously train our taste buds to like more vegetables.
3. Substituting non-caloric sweeteners for sugar — say drinking diet soda rather than regular — may help a bit on the margin with public health but, fundamentally doesn’t work because it feeds our desire for sweetness as opposed to retraining our palates to prefer other tastes.
4. Efforts to develop sweeter vegetable varieties or to get children to eat vegetables with cheese sauce, etc., are distractions from the key job: getting people to like tastes they are not used to and getting them to realize these tastes are good for them.
5. There is an urgency here. We do not have time to allow our bodies to adapt through the normal genetic process. We need to use our intellect and make choices that we are not driven to make by our own genetics. We are suited for living in a world characterized by a shortage of food and we live in a world of abundance. This leads to obesity and related complications.
It is a fascinating thesis and may well be true — what is not clear is whether it is possible on a mass scale.
We know that some individuals get “religion” and dramatically change their eating habits. We know that there are shifts that occur gradually as people age.
But do we have even one example of a whole nation dramatically changing its eating habits to be healthier?
It is fine to admonish people — but there are plenty of people who don’t make the effort to make sure their children speak French or German. What are we to do about those people?
Inevitably a campaign such as this seems likely to have class-based implications. In affluent countries, one reason poor people are poor is that, because of low education and relative isolation from knowledgeable social networks, they are not good at picking up societal messages as to what behaviors lead to success. It is the affluent and educated who are likely to have the presence of mind to hear messages such as this and act on them. We see this already… habits such as smoking and behaviors that lead to obesity are less common among the more affluent and educated.
What reasonable expectation can we possibly have that the general population will so dramatically change its behavior?
It is a fascinating topic, and we can’t wait to hear Professor Morini give her presentation at The New York Produce Show and Conference. In fact, she will be giving two. The main presentation will be given as part of the Educational Micro-Session Program on December 5, 2012 at Pier 94, and a second special version also will be adapted to the interests of the foodservice and culinary segment of the industry and presented as part of the “Ideation Fresh” Foodservice Forum on December 6, 2012, at the Sheraton New York Hotel.
Make sure you are there to hear this thought-provoking presentation; you can do so by registering here.
In addition, as mentioned above, Professor Morini will tailor her message to culinary and foodservice professionals at this year’s ”Ideation Fresh” Foodservice Forum, held on December 6. If you would like more information on this conference, please email us here.
If you are interested in coming early to The New York Produce Show and Conference and want to immerse yourself in international trade, we have a separate event — The Global Trade Symposium — held on Tuesday, December 4. If interested, please email us here.
Hotels are available at this link.
And we have negotiated a roster of travel discounts which you can find here.
There is also an extensive spouse program, which you can sign up for here.
And a roster of great tours can be signed up for here.
We invite you to come to The New York Produce Show and Conference and Celebrate Fresh! It’s also where the industry starts thinking in new ways. Come and be part of that conversation.
|
__label__1
| 0.512655
|
Hw Prototyping Jobs
show all
Looking for a mechanical engineer with experience in consumer hard goods. Experience and interest in ergonomics, product development, fastenings, mechanics, prototyping, and/or contemporary minimalist design a plus. You will be working closely with the designer to refine the engineered components and mechanics of the product - in this case, a high-end consumer backpack. Time commitment will be flexible- meetings as needed throughout the prototyping and production process. Ideally in the Greater Toronto Area.
Skills: Hardware Prototyping Mechanical Engineering Product Design
Hello, We need to build a platform that moves up and down that is controlled via Arduino (or similar system) and we need detailed instructions how to do it including code and wiring. Here is how should the setup look like: Platform attached to a thread fixed to stepper motor NEMA17 Stepper motor is controlled by control board (as mentioned - Arduino or similar). System will have 3 main inputs: A - number of motor turns “A” B - number of motor turns “B” C - sound input (microphone) And a few other inputs: D - lower endpoint E - upper endpoint F - ON/OFF switch A and B inputs are switches with a numerical value of how many turns should a motor move. Here can be switches (with 5 positions/values) or an lcd screen with buttons to adjust these values. Only five values for each switch will be used. C input gives a start for motor movement. Once the beep is heard - platform is moved up by the distance A+B. Once a double (or different tone) beep is heard, system moves the platform down by the distance B. After turning the machine ON, platform goes down to the lowest point until the lower endpoint button is reached. After the machine is turned OFF, platform goes up to the highest endpoint button is reached. After the machine hears a triple beep (or a special tone), platform goes up to the highest endpoint button is reached. We need to build such system and need detailed instructions including hardware parts, and software code.
Skills: Hardware Prototyping Electronic Design Electronics
Current Scenario: Please review the simplified block diagram. The Flora BLE is connected to the Flora MCU. The Flora BLE transmits at the rate of 9600 baud but even at this baud rate it drops a lot of values On the receiving side we have an nrf51 dongle that captured the data via COM port in to a file. Our windows application reads this file and processes the data further. Ideally we want to transmit at 115200 without any data loss. Required solution: BT native component selection that can replace the Flora BLE and stream in UART mode at 115200 and USB dongle for the PC than can receive it via USB/COM. Simple connections as shown in the schematic for ease of soldering / connecting. Can be any native BT profile. Should work on 3.7V Li-ion battery
Skills: Hardware Prototyping Bluetooth Device Driver Development Electronics
Here is the general story of my Hardware/Software project I have to make a Bluetooth mini microphone to capture heartbeats and send it to App (IOS). App should filter the noise the way we can hear our heartbeats through headphones clearly. My situation 1) I need hardware be shipped to the U.S after test 2) Agreed price is including all costs like components/materials and shipping 3) Agreed price will be paid after finishing the project. (No Upwork payment) 4) I have two months at max Thanks for understanding my situation
Skills: Hardware Prototyping iPhone App Development
Deliverable #1: Hardware prototype for two boards ( board A & board B) - it is acceptable to hand mount modules on prototype board and hand wire connections. Alternatively can create pcb. Board A has 2 modules on it. Board B adds a 3rd module. Each module requires power, antenna & high speed serial connections. Deliverable #2: Qty 15 demo boards: Take board A & B prototypes from Deliverable #1 and design custom PCBs. Then assemble, test and validate in 2 builds: Build 1 - 5 units Build 2 - remaining 10 units
Skills: Hardware Prototyping Computer Hardware Design
PCB Gerber design for a single board with the following features not greater in size than 2.5"X1.5". Battery and power requirements are not very critical right now but a 500 mAh, 3.7V battery should be able to drive the circuit. Our timeline is 10 days. - 2 low noise analog input channels with 10 bit ADCs sampling at 500 Hz each for typically measuring signal less than 1mV - Both analog channels need to have programmable gain with very low noise amplifier. - 9 DOF accelerometer - Temperature sensor (preferably digital IR). - HW timer circuit for on board analog signal analysis - Integrated BT4.0/WiFi chip for wireless communication to external devices and web E-ink display with touch screen and watch functionality (optional)
Skills: Hardware Prototyping Digital Signal Processing Hardware Troubleshooting PCB Design
|
__label__1
| 0.640179
|
I'm Aaron Meyer: a bioengineer, cyclist, and nerd.
You can also find me on Twitter, Github, LinkedIn, and Google Scholar.
Author Post: On Why We Build Models
The work from the final portion of my Ph.D. thesis is online today in Cell Systems, a brand new journal from Cell Press. Though nascent, the journal has already published exciting studies on the geospatial distribution of bacteria in cities, using CRISPR-Cas9 to rapidly engineer yeast metabolic pathways, and programming synthetic circuits in gut microbiota 1.
In it, we use differential equation modeling to understand how AXL (and very likely the other TAM receptor tyrosine kinases) senses phosphatidylserine (PtdSer)-presenting debris, a long-understood core function of the family. This was by far the most challenging undertaking of my Ph.D.–from utilizing the computational techniques to carefully designing the experimental measurements at each stage. The experience has taught me an enormous amount about the purpose and power of systems biology2.
Shou et. al. very recently described it best:
When scientists want to explain some aspect of nature, they tend to make observations of the natural world or collect experimental data, and then extract regularities or patterns from these observations and data, possibly using some form of statistical analysis. Characterizing these regularities or patterns can help scientists to generate new hypotheses, but statistical correlations on their own do not constitute understanding. Rather, it is when a mechanistic explanation of the regularities or patterns is developed from underlying principles, while relying on as few assumptions as possible, that a theory is born. A scientific theory thus provides a unifying framework that can explain a large class of empirical data. A scientific theory is also capable of making predictions that can be tested experimentally. Moreover, a theory can be refined in the light of new experimental data, and then be used to make new predictions, which can also be tested: over time this cycle of prediction, testing and refinement should result in a more robust and quantitative theory. Thus, the union of empirical and quantitative theoretical work should be a hallmark of any scientific discipline.
In a sense, kinetic rate equation models are fundamentally different from most data-driven approaches. These models of molecular systems make very few assumptions about underlying processes, meaning that we can not only learn from models that reproduce a behavior but often also from the ones that “break” and can’t fit the data. Relying only on experimental results doesn’t shield you from assumptions; in biology, experimental designs often rely on the underlying assumption that any one component of an organism has a unimodal relationship to the phenotype we observe. This is in part because the most simple (and often only feasible) experiments in one’s empirical toolbox are knockdown and/or overexpression, along with qualitative biochemical analyses. Biological systems are complex and nonlinear in their behavior though, and this initial view can quickly break down. For certain scales, a kinetic model can, in essence, be used as a scientific theory. Developed from underlying principles of rate kinetics and explaining the data we observe with as few assumptions as possible, it provides a unified framework for communication and further testing of our current understanding.
In the case of TAM receptors, manipulation by the addition or removal of ligand, receptor, or PtdSer has produced many observations. Some seemingly conflict with the previous mental model of particular factors being simply “activating” or “repressive.” The new theory/model that we propose, while being more complex, is maximally simple for the phenomena we wish to explain. With this new model, we can see how the previous mental model could be misleading, as complex, nonlinear relationships exist with respect to the timescale of one’s assay and factors such as PtdSer. That isn’t to say it is correct–it will always be wrong. In the near term, while we model only one receptor, AXL, the other TAM receptors MerTK and Tyro3 have critical roles both in normal physiology and cancer, and our understanding of how these receptors are similar or different is just beginning to be assembled. As TAM-targeted therapies are developed and evaluated in vivo, these models will help us understand how they work and develop even better therapies.
We need better methods at every step of this type of modeling, from construction and parameterization to understanding predictions3. Biology is complex, and mechanistic models such as these quickly become intractable on larger scales. Our study introduces the additional complexity of spatial scale, which makes each step of the process, as well as the corresponding experimental techniques, considerably more challenging. In the long term, I believe spatial organization of signaling will prove to be a critical component of understanding many cellular processes. We are going to need systems techniques to understand them.
1. I am incredibly excited by this journal’s creation. Systems biology has lacked a true “home” even as it has matured into an established field, and I am enthusiastic this will be it.
2. Ironically, I had to be convinced that such a project would be challenging enough to be interesting. After all, we learned about ODE modeling in undergraduate classes, it’s been applied for decades, and I would only be considering two proteins! Surely in the era of big data, a few rate parameters could be thrown together in a weekend and output some simulations of receptor activation. And rather than simulate a phenomena, why not just measure it experimentally?
3. Of course there are huge efforts to develop better tools for these purposes, but these remain difficult problems. Notable promising directions are rule-based models (such as BioNetGen) and brave attempts to try and accelerate Markov Chain Monte Carlo (e.g. DREAM). Truly rigorous modeling still remains a challenge even for the computationally adept however. It would be wonderful to have a rule-based framework that handled rigorous parameterization, spatial modeling through finite differences, compile-time detailed balance, and automatic differentiation (since all of these systems are stiff of course), but such a tool would be a considerable computational undertaking.
The Bad Luck of Improper Data Interpretation
An article and news summary is out in Science this week with a bold claim: that two-thirds of all cancers are due to baseline mutagenesis intrinsic to cell division, and not environmental factors or genetics. This is based on observed correlation between the number of stem cell divisions and incidence of cancer in various tissues. Certainly, such a conclusion would have immense consequences—it would emphasize treatment strategies over those of prevention, and refocus efforts away from understanding environmental toxins. Sadly, this conclusion is based on a frightening variety of errors in interpretation and basic math.
Most specifically, the two-thirds figure comes from the correlation coefficient between stem cell divisions and cancer incidence. While it is the case that the former explains 65% of the variation in cancer incidence between tissues, this does not translate to a percentage of cancer cases. This data is plotted on a log-log axis, and so distance along the plot is not linear. As the cancers with clear environmental factors are more common, the 65% claim is surely much lower.
Second, while this correlation might explain variation between tissues, it does not suggest the source of mutagenesis. Any factor that had similar effects throughout all tissues would vary this plot on the y-axis but have no effect on the correlation. Notably, as the data is plotted on a log axis, even for tissue-specific toxins many fold changes in the incidences of these cancers would still have no effect on the conclusions of this study.
Additional failures of interpretation in this study suggest little understanding of the data analysis involved. For example, k-means clustering a single variable lends little insight, and with outliers on either end is sure to form two groups with separation near the center of the range. This provides no evidence of there being two “classes” of cancer.
This article seems to be the product of lax peer review and pressure to over-interpret data to boost public interest. Both of these provide short-term gain to those involved but in the long run corrupt the scientific literature and erode public trust in science. Don’t do it!
Early Independence
Science doesn’t simply happen when money is spent; it requires immense effort, creative ideas, and dedicated time from well-trained scientists. Many factors can threaten these other requirements, such as funding instability and the aging of scientists. The average age at which an investigator receives their first R01, the mainstay grant of biomedical research, is now well into the mid-40’s. This drives many of the most talented individuals out of biomedical research, and curtails the benefit we as investors in biomedical research derive from those who remain, by limiting their ability to perform independent science during some of their most creative years.
To begin to address this one problem, the NIH has begun an experiment, the Early Independence Award, funding young investigators immediately after their Ph.D. so that they may undertake their own research independently. I’m excited to be officially joining this experiment, and hope you’ll see exciting work from the Meyer lab at MIT soon.
|
__label__1
| 0.959407
|
Search tips
Search criteria
Results 1-22 (22)
Clipboard (0)
Year of Publication
more »
1. Sound localization: Jeffress and beyond
Current opinion in neurobiology 2011;21(5):745-751.
Many animals use the interaural time differences (ITDs) to locate the source of low frequency sounds. The place coding theory proposed by Jeffress has long been a dominant model to account for the neural mechanisms of ITD detection. Recent research, however, suggests a wider range of strategies for ITD coding in the binaural auditory brainstem. We discuss how ITD is coded in avian, mammalian, and reptilian nervous systems, and review underlying synaptic and cellular properties that enable precise temporal computation. The latest advances in recording and analysis techniques provide powerful tools for both overcoming and utilizing the large field potentials in these nuclei.
PMCID: PMC3192259 PMID: 21646012
2. Organization of the Auditory Brainstem in a Lizard, Gekko gecko. I. Auditory Nerve, Cochlear Nuclei, and Superior Olivary Nuclei
The Journal of comparative neurology 2012;520(8):1784-1799.
We used tract tracing to reveal the connections of the auditory brainstem in the Tokay gecko (Gekko gecko). The auditory nerve has two divisions, a rostroventrally directed projection of mid- to high best-frequency fibers to the nucleus angularis (NA) and a more dorsal and caudal projection of low to middle best-frequency fibers that bifurcate to project to both the NA and the nucleus magnocellularis (NM). The projection to NM formed large somatic terminals and bouton terminals. NM projected bilaterally to the second-order nucleus laminaris (NL), such that the ipsilateral projection innervated the dorsal NL neuropil, whereas the contralateral projection crossed the midline and innervated the ventral dendrites of NL neurons. Neurons in NL were generally bitufted, with dorsoventrally oriented dendrites. NL projected to the contralateral torus semicircularis and to the contralateral ventral superior olive (SOv). NA projected to ipsilateral dorsal superior olive (SOd), sent a major projection to the contralateral SOv, and projected to torus semicircularis. The SOd projected to the contralateral SOv, which projected back to the ipsilateral NM, NL, and NA. These results suggest homologous patterns of auditory connections in lizards and archosaurs but also different processing of low- and high-frequency information in the brainstem.
PMCID: PMC4300985 PMID: 22120438
auditory nerve; ITD; cochlear nuclei; superior olive; reptile; lizard; tract tracing; Tokay gecko
3. Calcium-Binding Protein Immunoreactivity Characterizes the Auditory System of Gekko gecko
The Journal of comparative neurology 2010;518(17):3409-3426.
Geckos use vocalizations for intraspecific communication, but little is known about the organization of their central auditory system. We therefore used antibodies against the calcium-binding proteins calretinin (CR), parvalbumin (PV), and calbindin-D28k (CB) to characterize the gecko auditory system. We also examined expression of both glutamic acid decarboxlase (GAD) and synaptic vesicle protein (SV2). Western blots showed that these antibodies are specific to gecko brain. All three calcium-binding proteins were expressed in the auditory nerve, and CR immunoreactivity labeled the first-order nuclei and delineated the terminal fields associated with the ascending projections from the first-order auditory nuclei. PV expression characterized the superior olivary nuclei, whereas GAD immunoreactivity characterized many neurons in the nucleus of the lateral lemniscus and some neurons in the torus semicircularis. In the auditory midbrain, the distribution of CR, PV, and CB characterized divisions within the central nucleus of the torus semicircularis. All three calcium-binding proteins were expressed in nucleus medialis of the thalamus. These expression patterns are similar to those described for other vertebrates.
PMCID: PMC3170861 PMID: 20589907
cochlear nucleus; magnocellularis; laminaris; angularis; torus
4. Detection of Interaural Time Differences in the Alligator
PMCID: PMC3170862 PMID: 19553438
5. Vestibular nuclei characterized by calcium-binding protein immunoreactivity and tract tracing in Gekko gecko
Hearing research 2012;296:1-12.
Immunohistochemical techniques were used to describe the distribution of the calcium binding proteins calretinin, calbindin and parvalbumin as well as synaptic vesicle protein 2 in the vestibular nuclei of the Tokay gecko (Gekko gecko). In addition, tract tracing was used to investigate connections between the vestibular nerves and brainstem nuclei. Seven vestibular nuclei were recognized: the nuclei cerebellaris lateralis (Cerl), vestibularis dorsolateralis (Vedl), ventrolateralis (Vevl), ventromedialis (Vevm), tangentialis (Vetg), ovalis (VeO) and descendens (Veds). Vestibular fibers entered the brainstem with the ascending branch projecting to Vedl and Cerl, the lateral descending branch to Veds, and the medial descending branch to ipsilateral Vevl. Cerl lay most rostral, in the cerebellar peduncle. Vedl, located rostrally, was ventral to the cerebellar peduncle, and consisted of loosely arranged multipolar and monopolar cells. Vevl was found at the level of the vestibular nerve root and contained conspicuously large cells and medium-sized cells. Veds is a large nucleus, the most rostral portion of which is situated lateral and ventral to Vevl, and occupies much of the dorsal brainstem extending caudally through the medulla. VeO is a spherically shaped cell group lateral to the auditory nucleus magnocellularis and dorsal to the caudal part of Vevl. Vevm and Vetg were small in the present study. Except for VeO, all other vestibular nuclei appear directly comparable to counterparts in other reptiles and birds based on their location, cytoarchitecture, and connections, indicating these are conserved features of the vestibular system.
PMCID: PMC4101695 PMID: 23201031
6. Middle Ear Cavity Morphology Is Consistent with an Aquatic Origin for Testudines
PLoS ONE 2013;8(1):e54086.
The position of testudines in vertebrate phylogeny is being re-evaluated. At present, testudine morphological and molecular data conflict when reconstructing phylogenetic relationships. Complicating matters, the ecological niche of stem testudines is ambiguous. To understand how turtles have evolved to hear in different environments, we examined middle ear morphology and scaling in most extant families, as well as some extinct species, using 3-dimensional reconstructions from micro magnetic resonance (MR) and submillimeter computed tomography (CT) scans. All families of testudines exhibited a similar shape of the bony structure of the middle ear cavity, with the tympanic disk located on the rostrolateral edge of the cavity. Sea Turtles have additional soft tissue that fills the middle ear cavity to varying degrees. When the middle ear cavity is modeled as an air-filled sphere of the same volume resonating in an underwater sound field, the calculated resonances for the volumes of the middle ear cavities largely fell within testudine hearing ranges. Although there were some differences in morphology, there were no statistically significant differences in the scaling of the volume of the bony middle ear cavity with head size among groups when categorized by phylogeny and ecology. Because the cavity is predicted to resonate underwater within the testudine hearing range, the data support the hypothesis of an aquatic origin for testudines, and function of the middle ear cavity in underwater sound detection.
PMCID: PMC3544720 PMID: 23342082
PMCID: PMC3821004 PMID: 24265615
PMCID: PMC3821005 PMID: 24265616
9. Specialization for underwater hearing by the tympanic middle ear of the turtle, Trachemys scripta elegans
PMCID: PMC3367789 PMID: 22438494
underwater sound; evolution; cochlea; auditory brainstem response
11. Bigger Brains or Bigger Nuclei? Regulating the Size of Auditory Structures in Birds
Brain, Behavior and Evolution 2004;63(3):169-180.
Increases in the size of the neuronal structures that mediate specific behaviors are believed to be related to enhanced computational performance. It is not clear, however, what developmental and evolutionary mechanisms mediate these changes, nor whether an increase in the size of a given neuronal population is a general mechanism to achieve enhanced computational ability. We addressed the issue of size by analyzing the variation in the relative number of cells of auditory structures in auditory specialists and generalists. We show that bird species with different auditory specializations exhibit variation in the relative size of their hindbrain auditory nuclei. In the barn owl, an auditory specialist, the hind-brain auditory nuclei involved in the computation of sound location show hyperplasia. This hyperplasia was also found in songbirds, but not in non-auditory specialists. The hyperplasia of auditory nuclei was also not seen in birds with large body weight suggesting that the total number of cells is selected for in auditory specialists. In barn owls, differences observed in the relative size of the auditory nuclei might be attributed to modifications in neurogenesis and cell death. Thus, hyperplasia of circuits used for auditory computation accompanies auditory specialization in different orders of birds.
PMCID: PMC3269630 PMID: 14726625
Evolution; Auditory; Neuronal computation; Birds; Allometry
12. Evolution of a sensory novelty: Tympanic ears and the associated neural processing
Brain Research Bulletin 2007;75(2-4):365-370.
Tympanic hearing is a true evolutionary novelty that appears to have developed independently in at least five major tetrapod groups—the anurans, turtles, lepidosaurs, archosaurs and mammals. The emergence of a tympanic ear would have increased the frequency range and sensitivity of hearing. Furthermore, tympana were acoustically coupled through the mouth cavity and therefore inherently directional in a certain frequency range, acting as pressure difference receivers. In some lizard species, this acoustical coupling generates a 50-fold directional difference, usually at relatively high frequencies (2–4 kHz).
In ancestral atympanate tetrapods, we hypothesize that low-frequency sound may have been processed by non-tympanic mechanisms like those in extant amphibians. The subsequent emergence of tympanic hearing would have led to changes in the central auditory processing of both high-frequency sound and directional hearing. These changes should reflect the independent origin of the tympanic ears in the major tetrapod groups. The processing of low-frequency sound, however, may have been more conserved, since the acoustical coupling of the ancestral tympanate ear probably produced little sensitivity and directionality at low frequencies. Therefore, tetrapod auditory processing may originally have been organized into low- and high-frequency streams, where only the high-frequency processing was mediated by tympanic input.
The closure of the middle ear cavity in mammals and some birds is a derived condition, and may have profoundly changed the operation of the ear by decoupling the tympana, improving the low-frequency response of the tympanum, and leading to a requirement for additional neural computation of directionality in the central nervous system. We propose that these specializations transformed the low- and high-frequency streams into time and intensity pathways, respectively.
PMCID: PMC3269633 PMID: 18331899
Middle ear; Tympanum; Lizard; Frog; Hearing; Auditory; Brain stem
Developmental Neurobiology 2007;67(14):1957-1974.
PMCID: PMC3269634 PMID: 17918244
14. Modeling coincidence detection in nucleus laminaris
Biological Cybernetics 2003;89(5):388-396.
PMCID: PMC3269635 PMID: 14669019
15. Microsecond Precision of Phase Delay in the Auditory System of the Barn Owl
Journal of Neurophysiology 2005;94(2):1655-1658.
The auditory system encodes time with sub-millisecond accuracy. To shed new light on the basic mechanism underlying this precise temporal neuronal coding, we analyzed the neurophonic potential, a characteristic multiunit response, in the barn owl’s nucleus laminaris. We report here that the relative time measure of phase delay is robust against changes in sound level, with a precision sharper than 20 µs. Absolute measures of delay, such as group delay or signal-front delay, had much greater temporal jitter, for example due to their strong dependence on sound level. Our findings support the hypothesis that phase delay underlies the sub-millisecond precision of the representation of interaural time difference needed for sound localization.
PMCID: PMC3268176 PMID: 15843477
Journal of Neurobiology 2003;55(2):165-178.
PMCID: PMC3268178 PMID: 12672015
PMCID: PMC3260528 PMID: 12196590
18. Computational Diversity in the Cochlear Nucleus Angularis of the Barn Owl
Journal of Neurophysiology 2002;89(4):2313-2329.
The cochlear nucleus angularis (NA) is widely assumed to form the starting point of a brain stem pathway for processing sound intensity in birds. Details of its function are unclear, however, and its evolutionary origin and relationship to the mammalian cochlear-nucleus complex are obscure. We have carried out extracellular single-unit recordings in the NA of ketamine-anesthetized barn owls. The aim was to re-evaluate the extent of heterogeneity in NA physiology because recent studies of cellular morphology had established several distinct types. Extensive characterization, using tuning curves, phase locking, peristimulus time histograms and rate-level functions for pure tones and noise, revealed five major response types. The most common one was a primary-like pattern that was distinguished from auditory-nerve fibers by showing lower vector strengths of phase locking and/or lower spontaneous rates. Two types of chopper responses were found (chopper-transient and a rare chopper-sustained), as well as onset units. Finally, we routinely encountered a complex response type with a pronounced inhibitory component, similar to the mammalian typeIV. Evidence is presented that this range of response types is representative for birds and that earlier conflicting reports may be due to methodological differences. All five response types defined were similar to well-known types in the mammalian cochlear nucleus. This suggests convergent evolution of neurons specialized for encoding different behaviorally relevant features of the auditory stimulus. It remains to be investigated whether the different response types correlate with morphological types and whether they establish different processing streams in the auditory brain stem of birds.
PMCID: PMC3259745 PMID: 12612008
19. Maps of interaural time difference in the chicken’s brainstem nucleus laminaris
Biological cybernetics 2008;98(6):541-559.
Animals, including humans, use interaural time differences (ITDs) that arise from different sound path lengths to the two ears as a cue of horizontal sound source location. The nature of the neural code for ITD is still controversial. Current models differentiate between two population codes: either a map-like rate-place code of ITD along an array of neurons, consistent with a large body of data in the barn owl, or a population rate code, consistent with data from small mammals. Recently, it was proposed that these different codes reflect optimal coding strategies that depend on head size and sound frequency. The chicken makes an excellent test case of this proposal because its physical pre-requisites are similar to small mammals, yet it shares a more recent common ancestry with the owl. We show here that, like in the barn owl, the brainstem nucleus laminaris in mature chickens displayed the major features of a place code of ITD. ITD was topographically represented in the maximal responses of neurons along each isofrequency band, covering approximately the contralateral acoustic hemisphere. Furthermore, the represented ITD range appeared to change with frequency, consistent with a pressure gradient receiver mechanism in the avian middle ear. At very low frequencies, below400 Hz, maximal neural responses were symmetrically distributed around zero ITD and it remained unclear whether there was a topographic representation. These findings do not agree with the above predictions for optimal coding and thus revive the discussion as to what determines the neural coding strategies for ITDs.
PMCID: PMC3170859 PMID: 18491165
Auditory; Hearing; Sound localization; Sensory
20. Interaural timing difference circuits in the auditory brainstem of the emu (Dromaius novaehollandiae)
PMCID: PMC2948976 PMID: 16435285
21. Microseconds Matter
PLoS Biology 2010;8(6):e1000405.
This Primer focuses on detection of the small interaural time differences that underlie sound localization.
PMCID: PMC2893944 PMID: 20613856
22. Effect of Sampling Frequency on the Measurement of Phase-Locked Action Potentials
Phase-locked spikes in various types of neurons encode temporal information. To quantify the degree of phase-locking, the metric called vector strength (VS) has been most widely used. Since VS is derived from spike timing information, error in measurement of spike occurrence should result in errors in VS calculation. In electrophysiological experiments, the timing of an action potential is detected with finite temporal precision, which is determined by the sampling frequency. In order to evaluate the effects of the sampling frequency on the measurement of VS, we derive theoretical upper and lower bounds of VS from spikes collected with finite sampling rates. We next estimate errors in VS assuming random sampling effects, and show that our theoretical calculation agrees with data from electrophysiological recordings in vivo. Our results provide a practical guide for choosing the appropriate sampling frequency in measuring VS.
PMCID: PMC2955492 PMID: 20953249
vector strength; phase-locking; auditory brainstem; sound localization; temporal coding; circular statistics
Results 1-22 (22)
|
__label__1
| 0.984884
|
Close Window
Mechanisms of Placebo Effects
There has been a recent upsurge of interest in placebo effects (e.g., Blakeslee, 1998 a, b; Brown, 1998; Harrington, 1997; Holden, 2002; Moerman, 2001; Petrovic, Kalso, Petersson, and Ingvar, 2002). The word placebo (from the Latin, I shall please) has two related meanings: (1) a substance containing no medication but prescribed or given to reinforce a patient's expectation to get well; (2) an inactive substance or treatment used as a control in an experiment to test the effectiveness of a drug or medical treatment. Many reports show that placebos have significantly greater effects than giving no treatment, so rather than employing placebos simply as controls in experiments or clinical trials, there is increasing study of the mechanism(s) of placebo effects. As in many cases in biological psychology and biomedical sciences, no single mechanism accounts for all the effects.
Some of the proposed mechanisms are these: (1) As the text notes (pp. 241-242), it was found in the 1970s that placebo reduction of pain is mediated in part by endogenous opioids, demonstrated by the fact the effect could be reduced by the opioid-blocker naloxone. This suggested to some that the placebo effect is "real" because it is mediated by a known physiological mechanism. This could not be a complete explanation for placebo effects, because they occur not only for relief of pain, but also for other situations such as asthma attacks, where opioids would not normally relieve the symptoms. (2) It was also found in the 1970s that immunosuppressive effects can be conditioned to originally ineffective stimuli (p. 500). (3) The placebo might reduce stress, allowing the body to regain a natural, optimal level of functioning. Each of these mechanisms would be expected to be systemic, affecting the whole body, but cases were found in which the placebo effect held for only a specific part of the body. Thus, in an experiment in which a placebo in the form of a topical anesthetic was administered to one index finger and then shock was applied to both index fingers, most subjects reported less pain in the finger with the sham anesthetic (Montgomery and Kirsch, 1996). Such results support the interpretation that the expectancies of people cause placebo effects. The role of the basal amygdala in interpretation of stimuli and expectancies is discussed on pp. 483-485, and further work is to be expected on how expectations translate into bodily responses.
The variability of effects among placebo studies causes difficulties in accepting these effects. Moerman (2001) compared 117 double-blind placebo-controlled ulcer studies from all over the world. Doctors used the same drugs, the same placebo pills, and studied images of the stomach lining before and after treatment to rate effects. Among the studies, drugs caused improvement in 38-100%, whereas placebos worked from 0 to 100% of the time. The placebo effects were more variable than the drug effects, but among the studies the rates of healing for placebos and drugs correlated significantly (r=.40). The world average for placebo healing effects in these ulcer studies was 36%, and results for the United States were close to this value, yet placebos were effective in 59% of the patients in Germany but 22% in the neighboring counties of Denmark and the Netherlands, and only 7% in Brazil. To try to find whether national variation in placebo effectiveness is general across diseases, Moerman (2001) examined the results of controlled studies of treatments for moderate hypertension and for generalized anxiety disorder. Here the placebo effects for Germany were among the lowest for treatment of hypertension and middling for anxiety disorder, and no generality was found across nations. Differences in effectiveness of placebos have been attributed in part to cultural factors, including the differences in the enthusiasm and conviction with which physicians present the treatments, but the variability within nations indicates that this question is far from being solved.
In spite of the variability of results, Benson and Friedman (1996) urge physicians to harness the power of the placebo effect, since it is effective in so many situations, is safe and inexpensive and has withstood the test of time. Noting the negative connotations of the term "placebo effect," they suggest renaming it "remembered wellness."
Further understanding of the placebo effect is provided by a recent study in which PET brain imaging was used to compare the neural mechanisms involved in both opioid analgesia and placebo analgesia (Holden, 2002; Petrovic, Kalso, Petersson, and Ingvar, 2002). Six experimental conditions were included: heat pain and treatment with a rapidly acting opioid injected 40 sec. before the start of heat stimulation (pain-opioid [POP]), non-painful warm stimulation and opioid treatment (WOP) heat pain and placebo treatment with a saline injection (PPL), non-painful warm stimulation and placebo (WPL), heat pain only (P), and non-painful warm stimulation only (W). Heat pain was produced by pressing a metal stimulator at 48 degrees C on the back of the left hand for 70 sec. 48 degrees may not seem very hot, but the pressure on the back of the hand prevented reduction of heat by blood circulation, and subjects rated the pain an average of 65 on a scale where 100 meant unbearable pain (personal communication from Martin Ingvar, Feb. 18, 2002). The control stimulation was 38 degrees C. Although there was high inter-individual variation in placebo effectiveness among the 9 subjects, most showed lower pain ratings during the PPL condition than in the P condition.
Brain imaging showed that both opioid analgesia and placebo analgesia activated the rostral anterior cingulate cortex and a region in the pons. The authors suggest that in some cases cortical regions may exert control over analgesic systems of the brainstem, not only during opioid analgesia but also during placebo analgesia. Those subjects who showed a greater placebo effect also showed greater activation of the anterior cingulate cortex. Thus this study helps to understand a mechanism involved in the placebo analgesic effect.
The concept of effects of expectations on bodily processes has been extended to include the "nocebo effect" (from the Latin, I shall harm). This is the concept that an inactive substance or treatment can cause distress, illness, or even death (such as have been asserted to occur as a result of “voodoo” curses). Understandably, there has been much less research on the nocebo phenomenon than on the placebo effect. In one study, 48% of 40 asthmatics who were exposed to water vapor and told they were inhaling irritants or allergens experienced substantially increased airway resistance (Luparello et al., 1968). The twelve subjects who developed full-blown attacks were relieved by the same saline solution when it was presented as a therapeutic treatment. Thus, the same substance, presented differently, was either a nocebo or a placebo. Further experiments extended these findings (Luparello et al., 1970). Recently physicians have become concerned that nonspecific nocebo side effects of medications may distress patients, lead them to refuse to use prescribed drugs, and may cause physicians to discontinue what would otherwise be an appropriate therapy (Barsky, et al., 2002). They suggest that health care personnel can attempt to ameliorate nonspecific side effects to medications by identifying patients most likely to develop them and establishing a collaborative relationship with the patient to help understand and tolerate these bothersome but nonharmful symptoms.
Petrovic, P., Kalso, E., Petersson, K.M. and Ingvar, M. (2002). Placebo and opioid analgesia -- imaging a shared neural network. Sciencexpress. Available on Internet at http://alfpek.ingvar.com/pek.htm
|
__label__1
| 0.916965
|
POLICE are appealing for the rightful owners of suspected stolen property to contact them.
In separate incidents officers have seized property including medals, a bike and some stained glass window panels.
The Ridgeback black bike was seized from a man in Coxford who claimed he had found it but officers think it may have been stolen and are appealing for the owner to get in touch.
A number of medals have also been recovered which are thought to have been stolen during a burglary.
The six medals were awarded during World War Two and include the Battle of Britain Star, Africa Star, the Italy Star, the France and Germany Star, the Defence medal and the War medal.
Police are also hoping to trace the owners of some distinctive stained glass window panels that were found by officers as they searched a van.
Anyone who recognises any of the property can contact Helen Ward at Southampton Central police station on 023 8053 323.
|
__label__1
| 0.999572
|
In its attempts to bring investment to India, the country’s new government is facing a host of challenges. If it stays the course, its efforts should pay off.
or years, the phenomenon that domestic and global corporations and fund managers worried about most when considering investments in India—even more than its vacillating politicians and avaricious bureaucrats—was the unpredictability of the monsoon and the effect it has on India’s GDP growth.Their concern was hardly surprising: With 25% of India’s GDP and over two thirds of its population being directly dependent on the monsoon, the engine of the economy is fueled by rainwater.
During the fiscal year 2003-2004 (April-March), the Indian economy grew by 8.2%, driven by a 9.1% jump in agricultural production as a result of an abundant monsoon and higher industrial output. This year the rains have not
Already GDP growth expectations have been scaled down to 6.5% for fiscal year 2004-2005. But this figure assumes that there will be some agricultural growth. If the agricultural sector shows a negative growth for the year, the overall GDP growth number may have to be scaled down further.
The monsoon failure joins a string of unexpected events in 2004, ranging from the electoral defeat of the pro-reform NDA government to potential reversals on privatization, electricity and banking reforms—and promises of increased subsidies from a left-leaning government. While these developments rattled stock market investors, things are not as bleak as they appear.Within the ruling alliance there is no fundamental objection to continuing with the reform process, for example.“It is the pace of reforms which has changed and not the direction, and so far there has been no loss of confidence among investors,”says Ajit Ranade,group chief economist at the diversified industrial giant Aditya Birla Management Corporation.While the monsoon has an indirect impact on industrial demand, there are several mitigating factors. Both the industry and services sectors, which make up 75% of GDP, have proven to be very resilient and in recent years have shown strong growth even when monsoons have been poor. In 2002-2003, for example, India suffered the worst drought in 15 years, but GDP still grew by 4%, despite a 5.2% shrinkage in the agricultural sector. In fact, as India’s economy modernizes, the impact of the monsoon is diminishing significantly.
The failure of this year’s monsoon might throw macro calculations off for the next year, but it does not mean that foreign investment interest will decline.
“There is no dearth of opportunity in the Indian marketplace,” says Mahesh Vyas, managing director of the Center for Monitoring the Indian Economy (CMIE). “Investors, foreign and Indian alike, will have to see the opportunity for themselves and that the opportunity is much larger than they think.”
In sectors such as telecom, banking, insurance, IT-enabled services, petroleum and auto ancillaries, there has been a deluge of foreign investments.Recently,Singapore Technologies and Malaysia Telekom announced they would invest $220 million for a 33% stake in IDEA Cellular, India’s fifth-largest cellular company, the latest example of big-ticket investments in the Indian services sector. “Thanks to a robust manufacturing and years to reach $60 billion a year.This year has been even better: During the first two months of fiscal 2004-2005, exports grew by 25% over the same period last year. Export performance has been so buoyant that India has been running a current account surplus for the past three consecutive years, which, according to the Reserve Bank of India, reached an all-time high of 1.4% of GDP.
Unfortunately, the new government’s efforts to attract FDI and portfolio flows are being hindered by contradictory statements emanating from the different factions of the ruling alliance.The finance minister, Palaniappan Chidambaram, has announced increased equity ceilings in telecom to 74% and in civil aviation and insurance to 49% and the sale of a 5%
Ajit Ranade, Aditya Birla Management Corporation
services sector, the economy can safely grow at 6.5% even with a poor monsoon, and this growth rate is above the long-term trend-line growth,” says Ranade.
Export Market Flourishes
Potential investors are also reassured by the fact that India’s economy is becoming increasingly export driven, as companies achieve the scale and confidence to expand into new markets. For example, from a base of almost zero a few years ago, the automobile sector, including ancillaries, now exports $3.5 billion worth of vehicles and components.The petroleum sector has seen similar growth: Now it exports $3 billion worth of value-added products annually, including motor and aviation fuel.The IT sector has gone from a few hundred million dollars of exports in the mid-1990s to $10 billion in exports for 2003-2004.
Figures like these have helped India achieve 17% compound annual growth in exports for the past two consecutive stake in power company NTPC. But the government’s communist allies,backed by the trade unions, want these rescinded and further restrictions imposed on foreign investment. Undeterred, the government is sticking to its revised $15 billion annual FDI target—although it does not acknowledge that against the current target of $10 billion India received just $5 billion last year.
As yet, India does not have a clear plan for how it will achieve these figures, but it still wants to match the kind of capital flows received by China in recent years. “FDI can be used as a tool for growth, especially as India needs investment in new capacities. India offers great opportunity with skilled labor besides having a large domestic market,”says Vyas.
While the hurdle of political opposition can be easily overcome, the government’s FDI policy is still very cumbersome and desperately needs streamlining. “We have to create a climate to attract investment. We need to reduce the in-vestors’ points of contact with the bureaucracy, streamline the current requirements of multiple approvals, introduce a uniform FDI policy and not the sectoral kind that we have now, and introduce fiscal competition between states to attract investments,”says Ranade.Even in Mumbai, India’s financial capital, an investor setting up a call center operation needs 15 different sets of approvals from various local and state government bodies,underscoring the kind of bureaucracy that even controls sectors that are relatively uncomplicated to set up and run.
Both FDI and portfolio investments are linked to overall investor confidence in the system—not just political, but infrastructural as well. If the system and the environment are unstable or too cumbersome, then investments may not be so forthcoming. Foreign portfolio flows, though less stable, were robust last year and amounted to $11 billion—the highest ever inflow since India opened up its stock markets in 1995.With less favorable conditions prevailing this year, few are expecting to see similar inflows.The key factor that brought in last year’s bumper investment harvest was strong anticipated GDP growth.“There were several factors that drove GDP growth last year, which will be difficult to sustain in the current year. We had a confluence of favorable factors, such as low interest rates, low inflation, high business confidence and a great monsoon,” Ranade remarks.
One Country, Many Markets
The government knows well that faster GDP growth is critical to sustaining foreign investments, and its target is 7% to 8% growth for the next few years. This will be difficult to achieve without significant structural reforms. “Sustainable higher growth is a challenge now. What we need is a combination of reform plus infrastructure creation,” says Ranade.
A key recommendation of various think tanks and industry associations is the creation of a common economic market within India. Currently each state controls the flow of goods to and from other states, and each transit gener
ates taxes for the local and state governments concerned.This has gradually led to an institutionalized mechanism for corruption, delays and consequently increased the cost of goods flowing through the country.
The introduction of a value-added tax (VAT) in place of the cumbersome excise duty, state taxes and octroi (city taxes) regime is planned with a phased introduction from April 2005. It is expected to go a long way in ensuring better tax compliance, besides making indirect taxation uniform across the country. A key benefit expected from the introduction of VAT is that the tax-to-GDP ratio will improve substantially from the current dismal 9.5% (state taxes add another 6%). According to the recommendations of the task force on tax reform headed by the government’s chief economic adviser, Vijay Kelkar, the introduction of VAT will eliminate the revenue deficit by 2008-2009 and will increase GDP by 2%.
These measures will be crucial for building GDP, but the government also has to drive forward other projects, such as building new highways linking the major urban centers and creating other physical infrastructure such as ports and airports, as well as increasing public spending on healthcare and education. Some other recommendations being made to the government involve increasing the flow of credit to the small and medium-size enterprise (SME) sector and providing stable electricity at a lower cost to industries, thus leading to larger investment demand.The investment rate in India stands at around 20%—lower than the savings rate of 24%.According to the Planning Commission (which designs, implements and monitors five-year public investment plans), India needs a 28% investment to GDP ratio in order to sustain growth rates at 8% per annum, so there is a substantial investment gap that needs to be filled.
This is the minimum requirement for creating the environment for sustainable GDP growth and creating the right climate for domestic and foreign investment.The government also needs to ensure that people have the necessary spending power. Rural public works projects, major infrastructure projects, a stable tax regime and steadily increasing urban and rural incomes are providing the base for increasing consumer demand, which is a trigger for investment demand. “This year may not be great thanks to the drought, but if investors have a three- to five-year perspective, then things look good,”says Vyas.
Labor Reforms Itself
One common argument put forward as a stumbling block to foreign investment is the lack of labor reform, leading to lower foreign investor confidence. This could be a source of worry, considering that the biggest driver of FDI in India is labor outsourcing, whether it is in software services, auto components or textiles. But lack of labor reform or government willingness to consider allowing corporations the leeway to introduce a hire and fire policy is increasingly proving to be a non-issue.The reality is that Indian labor has proven itself to be very flexible.This fact has been demonstrated by events over the past few years.
cover_story_2 and successful voluntary retirement schemes abound both in corporate India as well as in the government sector. Over the past couple of years Tata Steel, the country’s largest private sector steel producer, reduced its workforce by more than 35%, from 78,000 to 50,000, while State Bank of India, India’s largest bank, reduced its workforce by 10%, or 23,500 employees, for example.
The worries for FDI investors in reality are not so many, since most global corporations are looking for specific skills or niches within which they can operate.The story for portfolio investors is different because they have a shorter time frame so they will be more concerned about short-term changes. Softer issues such as law and order play an important part in increasing confidence levels of all investors both foreign and domestic and irrespective of their investment holding time frame.
Political analysts and fund managers are unanimous that under the country’s new political masters, maintaining law and order will be a paramount concern and disturbances such as the communal flare-up witnessed a year ago in Gujarat will not recur. “The situation on the ground is getting better.The government, thanks to its social spending and various mega projects, is putting money into the hands of the population to spend,” says Vyas. People now increasingly have money to spend, and the law-and-order issues are being better appreciated. With so many changes already complete or under way, India probably already has the ingredients in place for making a lucrative investment pie that could whet the appetite of domestic and foreign investors.
|
__label__1
| 0.920202
|
Do you want to engage in discussions about health care, financial markets, or Social Security reform? Or perhaps you'd like to investigate why working women earn a fraction of what men earn, or the effectiveness of policies aimed at improving the environment, or even the impact of our economy's growing globalization. If you are interested in developing a coherent framework to answer questions like these, then you should consider studying economics at Hamilton.
Students who concentrate in economics learn to identify economic issues and problems, to form hypotheses and to gather and use data to test these hypotheses. They also learn how to formulate policies to deal with economic problems and how to analyze both the intended and unintended effects of these policies.
A concentration in economics requires the completion of five required courses and four electives within the department. Economics majors do need to take calculus prior to taking some intermediate-level courses but do not need to have taken any economics in high school. To earn a minor in economics, a student must complete four required courses and one additional economics course of her or his choice.
|
__label__1
| 0.990769
|
AN EAST Lancashire MP is warning constituents not to be entrapped by ‘legal loan sharks’ over the festive and new year period.
Hyndburn and Haslingden MP Graham Jones is urging residents to make use of credit unions and financial advice instead of high interest ‘payday loan’ firms.
He said: “A large number of people will be looking for credit over the festive period.
“However I want to offer a Christmas warning about using payday loan companies, or what are commonly referred to as legal loan sharks.
“Legal loan sharking risks putting people into a spiral of debt, with people having to take out other high-interest loans to pay off their existing ones. These companies prey on the poor and vulnerable.
“I am a member of Haslingden Credit Union, a much safer, fairer and more ethical means of lending money for a short term.”
|
__label__1
| 0.997092
|
First of 64 General Dynamics-built MeerKAT Radio Telescope Antennas ‘Stands-up’ in South Africa
General Dynamics's picture
Printer-friendly versionPrinter-friendly version
When all 64 MeerKAT antennas are operational, the instrument radio telescope will be sensitive enough to pick up a cell phone signal from Saturn.
NEWTON, N.C - General Dynamics SATCOM Technologies and Stratosat Datacom (Pty) Ltd., a South African company, have completed the installation of the first of 64 MeerKAT radio telescope antennas that will form the MeerKAT telescope array. The array is located in South Africa's Karoo region and will be a technologically advanced radio telescope designed to locate radio-frequency signals from the furthest reaches of the universe, possibly from the first stars and galaxies formed after the Big Bang. The MeerKAT array will constitute 25 percent of the Square Kilometer Array (SKA), which is scheduled for completion in 2024. Until the SKA is completed, the MeerKAT array will be the largest and most sensitive radio telescope in the southern hemisphere. Stratosat Datacom is the antenna prime contractor for the project
General Dynamics SATCOM Technologies' Duisburg, Germany, facility led the engineering and design of the MeerKAT antennas, including the incorporation of an 'indexer.' The addition of the indexer is unique on this type of antenna and allows scientists to easily and quickly change or "tune" the radio frequency of one or more antennas during any scientific experiment.The ability to alter the frequency of a radio telescope antenna without disrupting the entire array's performance is a significant technology advancement for radio telescopes.
With the completed antenna design, the Stratosat and General Dynamics SATCOM team is working closely with a number of South African fabricators, engineers and technicians to build and install the MeerKAT antenna array over the next three years.
"For more than 40 years, General Dynamics SATCOM Technologies has been helping scientists and astronomers unravel the mysteries of the universe," said Chris Marzilli, president of General Dynamics C4 Systems. "We are proud to be partnering with Stratosat in the construction of the MeerKAT array and look forward to the new and exciting discoveries it will yield."
Bolted to a specially constructed concrete platform, each 43-metric-ton MeerKAT antenna includes an 8.5-meter-tall pedestal that contains the control systems for the antenna. The pedestal supports a 13.5-meter main reflector with a boom-arm that holds a smaller reflector and the indexer mechanism. Once operational, radio signals from the antenna will be transmitted to a super-computer, which will create the visual map of the object or region in the universe being observed. The data received by a single MeerKAT antenna, in one day, will generate enough raw data to fill 15 million 64-GB devices.
MeerKAT in one of the precursor instruments for the SKA. The SKA project is an international effort to build the world's largest radio telescope, with a square kilometer (one million square meters) of collecting area. The scale of the SKA represents a huge leap forward in both engineering and research, and development towards building and delivering a unique instrument, with the detailed design and preparation now well under way. As one of the largest scientific endeavors in history, the SKA will bring together some of the world's leading scientists, engineers and policy makers. For more information about SKA visit
Since 1968, General Dynamics SATCOM Technologies has been a global leader designing and building some of the world's most advanced optical telescope mirror structures and radio telescope antennas.The company's technologically advanced antennas are found in astronomical observatories and scientific installations around the world, including:
• Lowell Observatory Discovery Channel Telescope (Arizona, U.S. A.), connecting millions of Discovery Channel viewers to real-time astronomy and research.
General Dynamics SATCOM Technologies also supplies commercial satellite antennas and related ground station products used by commercial communications companies and broadcast networks worldwide.
General Dynamics SATCOM Technologies is a part of General Dynamics C4 Systems, a business unit of General Dynamics (NYSE: GD).
News Source : First of 64 General Dynamics-built MeerKAT Radio Telescope Antennas ‘Stands-up’ in South Africa
|
__label__1
| 0.670914
|
Sign up
Here's how it works:
1. Anybody can ask a question
2. Anybody can answer
I came across an article by X and Y that is a nearly 100% self-plagiarised from an article by X several years earlier. A couple of words were changed, but that is it. The figures and tables are the same and so is the list of references. The titles are different. The publishers of the two journals are different.
To put it mildly, I am disappointed by the authors' unethical behavior, by the failure of referees to uncover the earlier work when reviewing relevant literature to assess novelty, and by the editor/publisher for apparently not bothering to use plagiarism detection software.
My first reaction was that I should report this case to the journal editor. Based on what I've heard from colleagues, however, they appear to not always take self-plagiarism seriously, presumably because it's a lot of unpleasant work. Should I therefore report this to PubPeer instead? Or to the editor and PubPeer?
share|improve this question
My purely personal 2 cents: falsification of results or plagiarism are the two capital crimes of science - the first, because it wastes everybody's time, the second because it takes away credit from someone else. Self-plagiarism is a nuisance because it assigns undeserved credit to oneself, but, frankly, it only has a real effect in publication-counting institutions/evaluations, and I am tempted to say that, if that's what they do, they deserve it. The evaluations I am involved in permit to list only a very limited number of publications, which makes self-plagiarism pointless. – Captain Emacs Feb 28 at 14:38
I personally find it disturbing that you suggest an editor should by default put all authors under suspicion by using "plagiarism detection software". A good peer review should easily uncover such a case anyway. – Zulan Feb 28 at 14:50
@Zulan: It seems to me that this is simply an insurance policy on the part of an editor to guard against referees not doing their job properly. If I were a journal editor, I would use plagiarism detection software as a matter of course. I would rather find out myself and reject an article prior to review than having to investigate and perhaps retract a published article. – G. L. Feb 28 at 15:10
@Zulan: Most referees do not have access to plagiarism-detection software and can only detect it by either manually searching the Internet for sentences, performing an intensive literature research or knowing the plagiarised texts sufficiently well. All of this is not their job, and can be easily performed by a software that should be the standard for publishers. As a referee, I would feel insulted and complain if a journal wasted my time by letting me review an article that a software could have easily detected to be plagiarised. – Wrzlprmft Feb 28 at 15:18
@Captain Emacs: Of course I agree that self-plagiarism is not equal to falsification of results or plagiarism. Nevertheless I feel that as reviewers and readers of articles, we cannot let self-plagiarism slide. I submit that as readers of the scientific literature, we have a duty to report such abuses. – G. L. Feb 28 at 15:19
up vote 60 down vote accepted
Taking the complaint public shames both the author and the journal, which may be counterproductive if the journal is responsible and willing to act promptly (mistakes do happen, even for very good journals).
I would thus recommend starting by reporting to the journal, which should have a procedure for dealing with such things. If the journal does not take you seriously or refuses to act, then take it public and shame both the author and the journal.
share|improve this answer
I suggest that you report this to the journal or editor first. If they fail to properly react to it, you can still escalate this by making it public. While the journal is likely to blame for not using proper plagiarism detection mechanisms, they are also likely the victim here, not the culprit.
Also, keep in mind that there may be reasons for this duplicate publication, e.g., one of the papers being published at a predatory publisher (see also this question which is essentially the same situation happening to a peer-reviewer).
share|improve this answer
Good point about predatory publishers. This is not the case here, however. The two journals have been published since the late 70's/early 80's. The publishers have reputable names. – G. L. Feb 28 at 15:27
@G.L.: The predatory publishers are only an example for some bizarre reason for this that you did not think of. Always give the accused a chance to explain. – Wrzlprmft Feb 28 at 15:42
You mean to say that if I have mistakenly published a paper in a predatory journal, then it is acceptable for me to republish it somewhere more reputable? Because that would not be ok in my book. – Federico Poloni Feb 28 at 21:48
While the journal is likely to blame for not using proper plagiarism detection mechanisms - In my field, I don't think we have any systemized mechanisms. The mechanism would be either the editor or referee realizes this, or someone else notices it later and reports it. – Kimball Feb 29 at 0:21
@Kimball You have got some standard solution to this that the publisher simply buys. No need to re-invent the wheel in your field. Many scientists are not ever aware these things exist. – yo' Feb 29 at 7:37
The case sounds serious. I have reported in a blog post (Plagiarism: everything but the title) an almost carbon-copy of a paper, but not by the same authors, which was withdrawn soon afterward.
First, check it is a regular peer-reviewed paper. Some "tutorial" or editorial papers may appear more than once: in Imperfect impact, the author provides a case of such a paper published 9 times, and the outcomes on terms of citations, with respect to journal impact factors.
Then, I would suggest you to first report to the (area) editor responsible for publication (generally mentioned on the published paper page). (S)he should get in touch with the corresponding author, or hand it over to higher authorities.
If you have no feeback (say in one month), copy the same letter to the journal editors in chief, copy to the publisher.
If you see no action, a last mail to X and Y before making stuff public would be fair. They would have the option to withdraw the paper by themselves.
P.S. the impact for authors is one more paper on their list, and potential more citations on careless databases, as shown in this figure from the above blog post (same paper published in different journals):
Effects of multiple publication
share|improve this answer
As far as I can tell, the later paper is a regular paper, not an invited paper that may have been afforded special privileges. (Even if it were, it should have cited the earlier paper....) You make a good point about contacting the authors if I don't hear back from the editor/editor-in-chief. – G. L. Feb 28 at 19:27
One of the authors might be aware of the issue. I have seen stories where one author adds other famous ones (without their consent) to help acceptance. One option, if you fell confident enough: start the process by a letter to the author. My opinion: it is better to start with the person in charge of the publication, the area editor – Laurent Duval Feb 28 at 19:39
There is no such thing as self-plagiarism.
If you have written something and the journals allow it and are aware of it, it is neither illegal nor prohibited by academic standards to publish and recycle it in 100 journals if it is your work.
I think you mean some other problems by the term "self-plagiarism":
• The author tries to sell his old work as new results obtained by paid work. That is fraud, pure and simple, especially if the author was funded to get new results.
• The author has published the work under the copyright terms of the journal. Normally the journal gets exclusive rights for publication and violating this terms is illegal.
Even if it is not forbidden, people do not try it except for a very good reason.
You are aggravating your academic colleagues because place for publishing is precious and you are wasting this space (There is nothing against trying several publishers as long as you retract the other submissions). You are also indicating that you are past your zenith in your academic career if you need to fall back on old work (In fact, I think of it more as terminal illness) or you come off as having a massive ego problem if you try to push your invaluable contributions into several journals. So your indignation is justifiable, especially because Journals will normally not allow duplicate publication and your suspicion is legitimate.
So contact the journal editor of the first publication and clear that up. It may be perfectly explainable what the author is doing, so take no action until you know what is going on.
ADDITION: Just for curiosity: PLL's "But it’s well-established now with the meaning of “re-using one’s own old work and presenting it as novel”" convinced me to ask Goggle's Ngram because I was curious about its usage.
Occurence of "self-plagiarism"
So the current usage in books is 45/100 000 000 instances. If we compare that the usage of the domain-specific, non-English word "Camellia"
Occurence of "Camellia"
Camellia occurs (at maximum) in 40/1 000 000 instances. Which means that "Camellia" is used approximately 100 times more than the "self-plagiarism" term. For fun, "Camellia" is comparable in usage to "trichloride".
It was used sporadically during the 1990s ("Duplicate publication" is definitly preferred) and only after the 2000s it became more prevalent and also used in titles and abstracts. The Wikipedia entry defined "self-plagiarism" 2005 and there it was specified later that this word was used mainly by biomedicine to summarize four categories: duplicate publication, copyright infringement, salami-slicing and use of own text modules. It must also be said that its usage is controversial for exactly this reasons,because it tries to subsume salami-slicing and the use of own text modules under a term which contains much more serious violations like duplicate publication or copyright infringement. So "self-plagiarism" is according to the "Committee on Publication Ethics" not equivalent to duplicate publication.
Sorry, but "self-plagiarism" seems to be neither as widespread or well-accepted as claimed nor is its usage uncontroversial.
share|improve this answer
I could not disagree more with two of your statements. First, if there is no such thing as self-plagiarism, why are there several posts and a tag in this forum? And why would it be discussed on Wikipedia and many other webpages? Second, you say that it is neither illegal nor prohibited by academic standards to publish and recycle something you've written in 100 journals. Any journal (I have published in) has required me to state that the work being submitted is original and has not been published or submitted elsewhere. – G. L. Feb 28 at 20:13
@G. L. Citation Wikipedia: "The concept of "self-plagiarism" has been challenged as being self-contradictory, an oxymoron and on other grounds." The reason is simple: Plagiarism is defined as using works of other people without consent or appropiation. The pink invisible unicorn has also a Wikipedia page, that does not mean that it exists or makes sense. And your second objection misses completely the cursive and the journals allow it and are aware of it statement and more comments below it. – Thorsten S. Feb 28 at 20:32
@ThorstenS.: your (and Wikipedia’s) argument that self-plagiarism is self-contradictory seems like saying that chamomile tea can’t exist because tea is defined as the species Camellia sinensis. Self-plagiarism is indeed different from plain plagiarism — so maybe it’s a badly-chosen term. But it’s well-established now with the meaning of “re-using one’s own old work and presenting it as novel”, and this meaning certainly makes sense and occurs all too often in practice. – PLL Feb 28 at 21:07
@PLL Sigh, not again a slidshod misnomer which becomes a standard word. I will at least not accept it as long as possible. I am afraid I am getting old. – Thorsten S. Feb 28 at 21:17
@ThorstenS. As the old joke goes: "Why do we drive on a parkway and park on a driveway?" Language is a messy affair and we don't get to dictate which words our culture assigns to concepts. – jakebeal Feb 29 at 3:40
Your Answer
|
__label__1
| 0.688303
|
Stopain Migraine Topical Pain Relieving GelStopain Migraine is the first topical migraine product on the migraine and is effective at relieving migraine pain.
Managing Headache PainFar and away, the most common headache is called the stress headache. So, what causes these stress, or tension, headaches?
Managing HeadachesThe most common type of headache is a stress headache and guess what? The most common cause is stress. But other causes are skipping meals, irregular sleep habits or certain foods.
More From CBS Philly
Submit Your Question
Listen Live
|
__label__1
| 0.535334
|
Search tips
Search criteria
Results 1-7 (7)
Clipboard (0)
Select a Filter Below
Year of Publication
Document Types
author:("vise, meikle")
1. Retinoschisin gene therapy in photoreceptors, Müller glia, or all retinal cells in the Rs1h−/− mouse
Gene therapy 2014;21(6):585-592.
X-linked retinoschisis, a disease characterized by splitting of the retina, is caused by mutations in the retinoschisin gene, which encodes a secreted cell adhesion protein. Currently, there is no effective treatment for retinoschisis, though viral vector-mediated gene replacement therapies offer promise. We used intravitreal delivery of three different AAV vectors to target delivery of the RS1 gene to Müller glia, photoreceptors, or multiple cell types throughout the retina. Müller glia radially span the entire retina, are accessible from the vitreous, and remain intact throughout progression of the disease. However, photoreceptors, not glia, normally secrete retinoschisin. We compared the efficacy of rescue mediated by retinoschisin secretion from these specific subtypes of retinal cells in the Rs1h−/− mouse model of retinoschisis. Our results indicate that all three vectors deliver the RS1 gene, and that several cell types can secrete retinoschisin, leading to transport of the protein across the retina. The greatest long-term rescue was observed when photoreceptors produce retinoschisin. Similar rescue was observed with photoreceptor-specific or generalized expression, though photoreceptor secretion may contribute to rescue in the latter case. These results collectively point to the importance of cell targeting and appropriate vector choice in the success of retinal gene therapies.
PMCID: PMC4047144 PMID: 24694538
Gene therapy; X-linked retinoschisis; AAV vectors; photoreceptors; Müller glia; cell targeting
2. AAV-Mediated, Optogenetic Ablation of Müller Glia Leads to Structural and Functional Changes in the Mouse Retina
PLoS ONE 2013;8(9):e76075.
Müller glia, the primary glial cell in the retina, provide structural and metabolic support for neurons and are essential for retinal integrity. Müller cells are closely involved in many retinal degenerative diseases, including macular telangiectasia type 2, in which impairment of central vision may be linked to a primary defect in Müller glia. Here, we used an engineered, Müller-specific variant of AAV, called ShH10, to deliver a photo-inducibly toxic protein, KillerRed, to Müller cells in the mouse retina. We characterized the results of specific ablation of these cells on visual function and retinal structure. ShH10-KillerRed expression was obtained following intravitreal injection and eyes were then irradiated with green light to induce toxicity. Induction of KillerRed led to loss of Müller cells and a concomitant decrease of Müller cell markers glutamine synthetase and cellular retinaldehyde-binding protein, reduction of rhodopsin and cone opsin, and upregulation of glial fibrillary acidic protein. Loss of Müller cells also resulted in retinal disorganization, including thinning of the outer nuclear layer and the photoreceptor inner and outer segments. High resolution imaging of thin sections revealed displacement of photoreceptors from the ONL, formation of rosette-like structures and the presence of phagocytic cells. Furthermore, Müller cell ablation resulted in increased area and volume of retinal blood vessels, as well as the formation of tortuous blood vessels and vascular leakage. Electrophysiologic measures demonstrated reduced retinal function, evident in decreased photopic and scotopic electroretinogram amplitudes. These results show that loss of Müller cells can cause progressive retinal degenerative disease, and suggest that AAV delivery of an inducibly toxic protein in Müller cells may be useful to create large animal models of retinal dystrophies.
PMCID: PMC3785414 PMID: 24086689
3. Intravitreal Injection of AAV2 Transduces Macaque Inner Retina
Intravitreally injected AAV2 transduced inner retinal cells in a restricted region at the macaque fovea. Because macaque and human eyes are similar, the results suggest a need to improve transduction methods in gene therapy for the human inner retina.
Adeno-associated virus serotype 2 (AAV2) has been shown to be effective in transducing inner retinal neurons after intravitreal injection in several species. However, results in nonprimates may not be predictive of transduction in the human inner retina, because of differences in eye size and the specialized morphology of the high-acuity human fovea. This was a study of inner retina transduction in the macaque, a primate with ocular characteristics most similar to that of humans.
In vivo imaging and histology were used to examine GFP expression in the macaque inner retina after intravitreal injection of AAV vectors containing five distinct promoters.
AAV2 produced pronounced GFP expression in inner retinal cells of the fovea, no expression in the central retina beyond the fovea, and variable expression in the peripheral retina. AAV2 vector incorporating the neuronal promoter human connexin 36 (hCx36) transduced ganglion cells within a dense annulus around the fovea center, whereas AAV2 containing the ubiquitous promoter hybrid cytomegalovirus (CMV) enhancer/chicken-β-actin (CBA) transduced both Müller and ganglion cells in a dense circular disc centered on the fovea. With three shorter promoters—human synapsin (hSYN) and the shortened CBA and hCx36 promoters (smCBA and hCx36sh)—AAV2 produced visible transduction, as seen in fundus images, only when the retina was altered by ganglion cell loss or enzymatic vitreolysis.
The results in the macaque suggest that intravitreal injection of AAV2 would produce high levels of gene expression at the human fovea, important in retinal gene therapy, but not in the central retina beyond the fovea.
PMCID: PMC3088562 PMID: 21310920
4. Changes in Adeno-Associated Virus-Mediated Gene Delivery in Retinal Degeneration
Human Gene Therapy 2010;21(5):571-578.
Gene therapies for retinal degeneration have relied on subretinal delivery of viral vectors carrying therapeutic DNA. The subretinal injection is clearly not ideal as it limits the viral transduction profile to a focal region at the injection site and negatively affects the neural retina by detaching it from the supportive retinal pigment epithelium (RPE). We assessed changes in adeno-associated virus (AAV) dispersion and transduction in the degenerating rat retina after intravitreal delivery. We observed a significant increase in AAV-mediated gene transfer in the diseased compared with normal retina, the extent of which depends on the AAV serotype injected. We also identified key structural changes that correspond to increased viral infectivity. Particle diffusion and transgene accumulation in normal and diseased retina were monitored via fluorescent labeling of viral capsids and quantitative PCR. Viral particles were observed to accumulate at the vitreoretinal junction in normal retina, whereas particles spread into the outer retina and RPE in degenerated tissue. Immunohistochemistry illustrates remarkable changes in the architecture of the inner limiting membrane, which are likely to underlie the increased viral transduction in diseased retina. These data highlight the importance of characterizing gene delivery vectors in diseased tissue as structural and biochemical changes can alter viral vector transduction patterns. Furthermore, these results indicate that gene delivery to the outer nuclear layer may be achieved by noninvasive intravitreal AAV administration in the diseased state.
Kolstad et al. evaluate the distribution of vector particles and transduction of AAV administered intravitreally in diseased versus healthy retinas. Whereas healthy retinas are not very receptive to vector penetration and transduction following intravitreal injection, in retinal degenerations the authors show improved and more extensive gene transfer.
PMCID: PMC3143418 PMID: 20021232
5. CLRN1 Is Nonessential in the Mouse Retina but Is Required for Cochlear Hair Cell Development
PLoS Genetics 2009;5(8):e1000607.
Author Summary
Usher syndrome (USH) is a progressive disease affecting two primary senses: vision and hearing. Often by the third decade of life, affected persons have lost the majority of their rod photoreceptors, which leads to night blindness and peripheral vision loss. Similarly, hearing loss often progresses into the third or fourth decade. By the fourth decade, patients typically approach legal blindness and hearing impairment continues to decline. The proteins that when mutated cause USH are frequently found in primary sensory cells, photoreceptor and hair cells, that directly respond to light and sound, respectively. Similar to other forms of USH, the mRNA coding for the protein responsible for USH type 3 (CLRN1) is expressed in cochlear hair cells of the inner ear. However, as demonstrated in the current study, and unlike other USH disease proteins in the retina, we show that the Clrn1 is expressed in glial cells in the retina (Müller cells) and is not expressed in the photoreceptors themselves. For reasons that remain unclear, the Clrn1 knockout mouse does not have a retinal degeneration phenotype but does become deaf soon after birth. In the current paper, we characterize the expression pattern in the retina and analyze the effects of removing the Clrn1 gene on vision and hearing.
PMCID: PMC2719914 PMID: 19680541
6. In vitro analysis of promoter activity in Müller cells
Molecular Vision 2008;14:691-705.
Rational modification of promoter architecture is necessary for manipulation of transgene activity and requires accurate deciphering of regulatory control elements. Identification of minimally sized promoters is critical to the design of viral vectors for gene therapy. To this end, we evaluated computational methods for predicting short DNA sequences capable of driving gene expression in Müller cells.
We measured enhanced green fluorescent protein (eGFP) expression levels driven by “full-length” promoters, and compared these data with computationally identified shorter promoter elements from the same genes. We cloned and screened over 90 sequences from nine Müller cell-associated genes: CAR2, CD44, GFAP, GLUL, PDGFRA, RLBP1, S100B, SLC1A3, and vimentin (VIM). We PCR-amplified the “full-length” promoter (~1500 bp), the proximal promoter (~500 bp), and the most proximal evolutionarily conserved region (ECR; 95–871 bp) for each gene, both with and without their respective 5′ untranslated regions (UTRs), from C57BL/6J mouse genomic DNA. We selected and cloned additional ECRs from more distal genomic regions (both 5′ and 3′) of the VIM and CD44 genes, using both mouse and rat (Sprague-Dawley) genomic DNA as templates. PCR products were cloned into the pFTMGW or pFTM3GW lentiviral transfer vectors. Plasmid constructs were transfected into rat (wMC) or human (MIO-M1) Müller cells, and eGFP expression levels were evaluated by fluorescence microscopy and flow cytometry. Selected constructs were also examined in NIH/3T3 and Neuro-2a cells.
Several ECRs from the nine Müller cell-associated genes were able to drive reporter gene expression as well as their longer counterparts. Preliminary comparisons of ECRs from the VIM and CD44 genes suggested that inclusion of UTRs in promoter constructs resulted in increased transgene expression levels. Systematic comparison of promoter activity from nine Müller cell-expressed genes supported this finding, and characteristic regulation profiles were evident among the different genes tested. Importantly, individual cloned promoter sequences were capable of driving distinct levels of transgene expression, resulting in up to eightfold more cells expressing eGFP with up to 3.8-fold higher mean fluorescence intensity (MFI). Furthermore, combining constructs into single regulatory “units” modulated transgene expression, suggesting that secondary gene sequences provided in cis may be used to fine-tune gene expression levels.
In this study, we demonstrate that computational and empirical methods, when used in combination, can efficiently identify short promoters that are active in cultured Müller cells. In addition, the pFTM3GW vector can be used to study the effects of combined promoter elements. We anticipate that these methods will expedite the design and testing of synthetic/chimeric promoter constructs that should be useful for both in vitro and in vivo applications.
PMCID: PMC2330062 PMID: 18437242
7. Functional promoter testing using a modified lentiviral transfer vector
Molecular Vision 2007;13:730-739.
The importance of retinal glial cells in the maintenance of retinal health and in retinal degenerations has not been fully explored. Several groups have suggested that secretion of neurotrophic proteins from the retina's primary glial cell type, the Müller cell, holds promise for treating retinal degenerations. Tight regulation of transgene expression in Müller cells is likely to be critical to the efficacy of long-term neuroprotective therapies, due to the genetic heterogeneity and progressive nature of retinal disease. To this end, we developed a modified lentiviral (LV) transfer vector (pFTMGW) to accelerate the testing and evaluation of novel transcriptional regulatory elements. This vector facilitates identification and characterization of regulatory elements in terms of size, cell specificity and ability to control transgene expression levels.
A synthetic multiple cloning site (MCS) which can accept up to five directionally cloned DNA regulatory elements was inserted immediately upstream of an enhanced green fluorescent protein (eGFP) reporter. A cytomegalovirus (CMV) promoter, required for tat-independent viral packaging, is located around 2 kb upstream of the eGFP reporter and is capable of directing transgene expression. A synthetic transcription blocker (TB) was inserted to insulate the MCS/eGFP from the CMV promoter. We evaluated eGFP expression from pFTMGW and control constructs using flow cytometry and quantitative reverse transcriptase polymerase chain reaction (RT-PCR). We also tested and compared the activity and cell specificity of a computationally identified promoter fragment from the rat vimentin gene (Vim409) in transfection and lentiviral infection experiments using fluorescence microscopy.
Transfection data, quantitative RT-PCR, and flow cytometry show that around 85% of expression from the CMV promoter was blocked by the TB element, allowing direct evaluation of expression from the Vim409 candidate promoter cloned into the MCS. Lentiviruses generated from this construct containing the Vim409 promoter (without the TB element) drove robust eGFP expression in Müller cells in vitro and in vivo.
The TB element efficiently prevented eGFP expression by the upstream CMV promoter and the novel MCS facilitated testing of an evolutionarily conserved regulatory element. Additional sites allow for combinatorial testing of additional promoter, enhancer, and/or repressor elements in various configurations. This modified LV transfer vector is an effective tool for expediting functional analysis of gene regulatory elements in Müller glia, and should prove useful for promoter analyses in other cell types and tissues.
PMCID: PMC2765473 PMID: 17563724
Results 1-7 (7)
|
__label__1
| 0.51789
|
Proposition 2
To place a straight line equal to a given straight line with one end at a given point.
Let A be the given point, and BC the given straight line.
java applet or image
It is required to place a straight line equal to the given straight line BC with one end at the point A.
Post. 1, I.1.
Join the straight line AB from the point A to the point B, and construct the equilateral triangle DAB on it.
Produce the straight lines AE and BF in a straight line with DA and DB. Describe the circle CGH with center B and radius BC, and again, describe the circle GKL with center D and radius DG.
Since the point B is the center of the circle CGH, therefore BC equals BG. Again, since the point D is the center of the circle GKL, therefore DL equals DG.
And in these DA equals DB, therefore the remainder AL equals the remainder BG.
But BC was also proved equal to BG, therefore each of the straight lines AL and BC equals BG. And things which equal the same thing also equal one another, therefore AL also equals BC.
Therefore the straight line AL equal to the given straight line BC has been placed with one end at the given point A.
This is a very clever construction to solve what seems to be a simple problem. One would like simply to slide the line BC along so that one end coincides with the point A. But there is no motion in the geometry of Euclid. There is something like motion used in proposition I.4, but nothing is actually moved there. The only basic constructions that Euclid allows are those described in Postulates 1, 2, and 3. Euclid then builds new constructions (such as the one in this proposition) out of previously described constructions. So at this point, the only constructions available are those of the three postulates and the construction in proposition I.1, and Euclid uses all four here.
Another, different, expectation is that one might use a compass to transfer the distance BC over to the point A. It is clear from Euclid’s use of postulate 3 that the point to be used for the center and a point that will be on the circumference must be constructed before applying the postulate; postulate 3 is not used to transfer distance. Sometimes postulate 3 is likened to a collapsing compass, that is, when the compass is lifted off the drawing surface, it collapses.
It could well be that in some earlier Greek geometric theory abstracted compasses that could transfer distances. If that speculation is correct, then this proposition would be a late addition to the theory. The construction of the proposition allows a weaker postulate (namely postulate 3) to be assumed.
Construction steps
When using a compass and a straightedge to perform this construction there are more circles drawn than shown in the diagram that accompanies the proposition. These are the two circles needed to construct the equilateral triangle ABD. One side, AB, of that triangle isn’t necessary for the construction.
Altogether, four circles and two lines are required for this construction.
java applet or image
Use of Proposition 2
The construction in this proposition is only used in Proposition I.3.
Note that this construction assumes that all the point A and the line BC lie in a plane. It may also be used in space, however, since Proposition XI.2 implies that A and BC do lie in a plane.
|
__label__1
| 0.973823
|
Expert Analysis: Bill S. 978
GamePolitics Contributing Editor and Maryland intellectual property attorney Daniel Rosenthal offers and in-depth analysis of Bill S. 978 (also known as the "anti-streaming bill") in this guest editorial.
S.978, the "anti-streaming bill" has been introduced in Congress, apparently in response to the White House’s Intellectual Property Enforcement Legislation Recommendations white paper (PDF), which recommended to Congress that they should amend the Copyright Act to "clarify that [copyright] infringement by streaming . . . is a felony in appropriate circumstances." While that seems innocuous enough on its face, the bill presented by the bipartisan trio led by Sen. Klobuchar is deeply flawed for a number of reasons.
Let’s start by addressing the number one issue I see with people misreading the bill. S.978 has two separate and distinct parts. Paragraph (a) addresses the penalties for criminal infringement; while Paragraph (b) addresses the infringing actions that lead to those penalties. In other words, although the provisions of (a) are listed first, they do not actually apply until an action covered under (b) takes place. So in your head, read (b) first, then go back to (a). Next, we need to look at what the bill actually does. Paragraph (b) makes 17 U.S.C. 506, the criminal provisions of the Copyright Act, also apply to streaming (written as "public performance").
First, when you look at the overall picture for content consumers, you’re seeing a narrowing of our rights without any real payoff. At the same time this anti-streaming bill is coming out, we’ve also got ISP’s engaging in a self-censorship policy with regard to allegations – not even proof — of copyright infringement (the so-called "six strikes rule"). So we already have to be on our toes that our ISPs will throttle or cut our access without a fair means of recourse, or sufficient market alternatives. Now, on top of that, we have to worry about not just the content, but the method of socially sharing that content. Looking at the big picture, it’s one hit after another — ISP’s fighting against net neutrality, ISPs being able to monitor and restrict your data consumption without a legal judgment, and now the anti-streaming bill giving the copyright industry an open door to come after innocent users of services like or Viddler with criminal charges. It’s an erosion of our rights, and to what end? What are consumers getting out of this? Nothing — consumers will see absolutely zero benefit from this whatsoever, and given the transnational nature of software piracy, it will have minimal effect in its supposed purpose.
Second, the bill is horridly vague. So far, the chief defense that I’ve seen of S.978 is that it only applies to "willful" infringement. Let me tell you — that’s not a difficult standard to achieve. Willfulness in a copyright infringement action is not that difficult to prove, and can be inferred from the circumstances in a case. This bill would have the effect of forcing consumers to prove that they were not acting willfully — because any attorney worth their salt will be able to make a sufficient argument via circumstantial inference that the consumer’s actions were willful by saying "Look, he/she intentionally typed in the URL and uploaded a video for broadcast. They didn’t just trip and fall and faceroll the proper set of keyboard commands to share this video, there was intent to stream it to others." From there, it becomes YOUR duty to counter that argument; yet another burden on the consumer.
The other main defense that I’ve seen is that casual users will not be affected because the total economic value of the performances must be greater than $2500, or the fair market value of the licenses necessary must be greater than $5000. This too, falls flat as a defense. These minimums exist to provide for an increased penalty (minimum of three years) for those infringers acting for commercial gain. However, my reading of the law is that this does not replace the existing requirements for criminal infringement, but rather supplements them. So basically, even without meeting the dollar requirements under S.978, you could still be criminally prosecuted for streaming — you’d just get three years instead of five. Yay (My interpretation, by the way, appears to be shared by other cyberlaw-oriented attorneys: "S. 978 Sending Illegal Streamers up the River").
Furthermore, the minimum dollar values in the criminal provisions are ridiculously easy to meet. For example, if even 100 people watch a stream of a game (not unreasonable even for an amateur these days), and the court determines that the fair market value of a license is $50 (again, not unreasonable, given that the supposedly infringing content is the game itself being rebroadcast in video form), the economic burden is more than met. Enjoy your felony conviction and 5+ years in prison. As well, the bill fails to define what standards will be used to determine the economic value of the performance, leaving it up to the attorneys to fight it out. While the copyright industry can afford to spend dozens of man-hours drafting complex arguments in favor of their position, most defendants cannot afford that luxury (even at my very reasonable rates!) and most criminal defense attorneys are not familiar with copyright law. So the very vagueness of the bill itself serves as a further deterrent against consumers.
The vagueness doesn’t end there. What constitutes a "public performance" (per the bill) in the digital age? It is a term that dates back even before the Copyright Act of 1974, There have been reasonable arguments made that a monitor at a crowded LAN party could constitute a public performance. Many LAN cafes use streaming content in their games. But the law makes no exception for such a thing. What about spectator broadcasting of competitive gaming and e-sports? The law, as written, pushes the burden on the end-consumer of content to make legal assumptions as to the economic or market value of content they view before they actually view it. What about the "10 instances in a 180 day period" rule. Who is supposed to track that? The U.S. Government is not going to do it for you; the copyright holders who would be the plaintiffs are not neutral parties….every little bit of vagueness in this bill has the effect of emboldening and protecting the copyright industry and putting the end consumer at a disadvantage.
Finally, the bill has the added effect of harming smaller (particularly indie) developers. Regardless of whether the developer intends to sue over things like speed runs, "let’s play" videos, and gameplay reviews, the mere fact that they could do so acts as a chilling effect on the video-producing community. So companies like TGN and Machinima will be facing possible criminal liability with every video they produce — videos that directly assist the marketing teams of these smaller companies and help grow their player-base. You can bet on the copyright industry saying to them "I don’t care if you think it is fair use; if you don’t obtain a license from us, we’re going to demand criminal prosecution against you with the increased penalties for commercial infringement. Pay up or enjoy your felony trial, sucka."
There is a lot to be concerned about with S.978. Unlike the recent Supreme Court case in Brown v. EMA, where there were clear signs on how the Court was likely to rule, the future of S.978 is much more uncertain. Despite a Congress that seems to be divided on partisan lines, the bill enjoyed bipartisan support going through the Senate Judiciary Committee (Sens. Klobuchar and Coons are Democrats, Sen. Cornyn is a Republican). And presumably the bill seeks to implement the White House’s planned policies on IP enforcement, giving it some degree of administration support. Whether that is helpful or not with this Congress is a completely different question, but it certainly means that this is a bill to keep a very, very close eye on.
Image via.
Comments are closed.
|
__label__1
| 0.714706
|
The Vampire Armand Horror Movies - Page 16 of 25
(197) Results for "The Vampire Armand" Page 16/25
Displayed in "relevance" order with titles such as Avengers: Age of Ultron, Jesus Christ Vampire Hunter, Killing Car, My Demon Lover, Bloodsucking Bastards, Loved Ones, Unfriended, Pride and Prejudice and Zombies. Narrow search by using keywords and movie year to improve relevance.
Avengers: Age of Ultron
Avengers: Age of Ultron (2015)
Avengers: Age of Ultron (2015) is an American superhero action adventure film that was based on the Marvel Comics superhero…
Jesus Christ Vampire Hunter
Jesus Christ Vampire Hunter (2001)
Killing Car
Killing Car (1993)
KILLING CAR is one of Jean Rollin's most unusual films and is a real departure from the vampire theme for…
My Demon Lover
My Demon Lover (1987)
My Demon Lover (1987) is an American fantasy comedy movie that was one hour and a half long. Director Charlie…
Bloodsucking Bastards
Bloodsucking Bastards (2015)
Bloodsucking Bastards (2015) is an American comedy horror film that has a run time of 86 minutes. Director Brian James…
Loved Ones
Loved Ones (2009)
Unfriended (2014)
Unfriended (2014) is an American found footage supernatural horror movie that is also known as Offline (2014) and was initially…
Pride and Prejudice and Zombies
Pride and Prejudice and Zombies (2016)
Pride and Prejudice and Zombies (2016) is an American romance action horror film that I was looking forward to seeing…
|
__label__1
| 0.997417
|
Top Definition
When everything in the universe was created. Also, the time when many various things happened.
I started my period last Thursday.
#thursday #period #menstruation #creationism #schmuckythecat
Goddess_Freyaによって 2008年05月05日(月)
Represents a measure of time, being the long-term memory of popular culture (and sixteen year old girls in particular), since both seem to have trouble recalling anything that happened before last Thursday.
As a span of time, Last Thursday lies somewhere between a hundred years ago and the present, and is always followed by last Friday.
It is widely accepted that anything that did not take place this week took place Last Thursday. That is unless this event took place back in the day, which is of course a Wednesday.
#last #thursday #time #c.r.a.f.t. #wednesday #raptor jesus
EM3RG3NCYxによって 2009年03月02日(月)
|
__label__1
| 0.650779
|
Distance Between Buhl, ID and Ocean Shores, WA
How many miles? 706 Miles / 1136 Km
How many times? 11 hours 7 mins
Distance, Gas Consumption and Emission Notes
Distance from Buhl, ID to Ocean Shores, WA is 706Miles or 1136 Km. You can get this distance about 11 hours 7 mins. If you want to planning travel with plane for 552 Miles or 887 Km, You can get this distance about 1 hours 40 mins .
A car with an average MPG will needs 32.69 gallons of gas to get the route between these points.
The estimated cost of gas to get between Buhl, ID and Ocean Shores, WA is $74.21.
During the route, an average car will release 640.46 pounds of CO2 to the atmosphere. Your carbon footprint is 0.91 pounds of CO2 per mile.
* Average US MPG used for calculations is 21.6 MPG.
* Coordinates of Buhl, ID is 42.5990714, -114.7594946 and coordinates of Ocean Shores, WA is 46.9736986, -124.1562852
|
__label__1
| 0.931038
|
Not a member? Existing members login below:
The Wise Investor
which he traded for grain. Time passed, and it became
apparent that other people, too, had special skills of their
own, and particular products they liked to make. More
trading began, and soon there was an active and healthy
trade between the families. This trade benefited everyone
involved, although it soon became apparent that some people
were wiser in trade than others, and some seemed to
accumulate more grain over time than their neighbours.
As the trading of goods expanded, it soon became
obvious that there were other needs, as well. Some people
had need of items for short periods of time, such as a
borrowed plough while the their main plough was under
Many items were lent and borrowed. In return for
borrowing an item, the borrower would give the lender some
sacks of grain. The item would be returned, however the
lender would retain the grain as compensation for not having
use of the item. Soon, there was a thriving exchange of
items on loan, and a corresponding flow of grain in exchange
for the loan of the items.
Trade in ploughs, grain, cut wood and many other
products had been going on in the valley for some time,
along with lending of tools and machinery in return for fees.
The families found that they were all better off, as the
people who were best at each job were the ones who were
doing it for all. One year, however, a tragic accident
occurred. Three young men from one family were fishing in
the river, when a landslide crashed down the side of the
valley and killed all three. All the people the valley mourned
the tragic event. When the mourning was over, the family of
the boys was in serious trouble.
It was harvest time, and the youngest generation was not
quite old enough to complete the harvest by themselves.
Without the full harvest, the family would be critically short
of grain. Some families offered help, but it was their harvest
time as well and they could ill afford to spend the extra time
to help the grieving family.
|
__label__1
| 0.991965
|
Northern Ireland
How Is The Food In Northern Ireland?
Theresa Albert | Posted 04.11.2016 | Canada Travel
Theresa Albert
When Tourism Ireland invited me on a Foodie Tour of Northern Ireland, my first thought was "I can boil my own potatoes and I don't eat deep fried foods." They were only too happy to show me that my concept of Irish food is outdated and how far their culinary world has come.
|
__label__1
| 0.990613
|
Kheper Home | Metaphysics Main Page | Topics Index | New | Search
Parent nodes: Transcendent
Sibling nodes: The Unmanifest Absolute | The Manifest Absolute | The Noetic Absolute | The Infinite-Eternal - Planes and Hypostases of the Absolute | The Absolute Reality - Philosophical Thesis | Formless, Emptiness, Mystery - Professor Andrew Wilson - readings from world religions | The Transcendent, All-Pervasive Reality - Professor Andrew Wilson - more readings from world religions | Monism | Eastern Philosophy | Mysticism
Author's note (21 Dec 09) This page was originally written as part of - and has been relocated from - my "Integral Paradigm" series (original url). It reflectys an earlier phase of my understanding and gnosis, in which I still considered the nondual Reality the highest, and hence that the Ultimate must in some way be Unmanifest. This is basically a perennialist position which stems from Vivekananda's Neo-Vedanta, and derivative worldviews such as Guenon-Schuon Traditionalism (Neo-Sufi), Huxleyan Perennial Philosophy (strongly based on Vivekananda), Daist Advaito-Buddhism, and Wilberian Integralism (the latter heavily influenced by Da Free John). However, Sri Aurobindo has pointed out (I don't have the actual quote on me atm, it is in The Life Divine) that it is the mental being that conceives the Supreme as nonbeing or void (via negatia). So this represents only a Mental stage of Realisation, which is transcended through Higher Realisation and beyond. Sri Aurobindo's Integral philosophy is able to acknowledge all experiences and realisations, rather than subordinate the theistic to the nondual, or the nondual to the theistic. The following page therefore has been modified and updated to reflect this larger perspective.
The Transcendent Absolute Reality
The Transcendent Absolute Reality means the Absolute Reality as The Transcendent, and vice versa. As pointed out in the introductory notes, this represents a mental (jnana yoga) realisation; which is not the Absolute or the Supreme in its fullness. This partial understanding can be attained through Accounts in traditional religious literature, and Contemporary accounts of mystical experience (the universality and ubiquity of the monistic state), as well as Philosophical-Phenomenological reasoning ("Cartesian Monism").
From this perspective - i.e. Gnosis, Intermediate Zone, and (initial or teh first stage of) Realisation or Authentic Enlightenment, Reality in Itself, i.e. Reality as it appears without the blinkers of conceptual thought and psycho-physical consciousness, is infinite, eternal, limitless indivisable perfection. This Reality has been given many names - e.g. God, Self, Tao, Energy, Void, etc. Some of these names are stupid, others are good. For example, calling this Reality God (as some religious people do) or Energy (as some New Age people do) is stupid, because Energy is a quality, not an absolute, and God is generally thought of as a supreme being seperate from us, whereas Reality is us.
For the sake of convenience, I have used Plotinus' term "the Absolute", and Sri Aurobindo's term "the Supreme" as synonyms for Reality in Its Original Unmodified nature (which is its nature anyway, even in the midst of manifestation and duality).
The Neoplatonic term "hypostases" (underlying state) is used to designate the realities that are derived from that original Supreme, and at the same time are aspects of It.
Reality in Itself
Note (24 September 2009 or thereabouts, slightly revised 1 Jan 2010): This section originally incorpoarted material on metaphysical speculation from earlier pages in the old Kheper version 1 - The Nature of Realities | Kheper version 2 - The Integral Paradigm (first version) series, but as my ideas have developed since then, I originally intended like at some point to write an updated version, emphasizing "Thusness". Since then I realised there was no need for that, as the topic can equally be described under Realisation, Nonduality, Divinisation and other pages. Of these, Realisation refers to what is generally called "Enlightenment" (although I now avoid using this word because it has been so abused by fake "gurus"), Nonduality refers to Thusness experienced through impersonal jnana (Self-Realization) rather than personal bhakti (I need to set up a page for God-Realization), and Divinisation is the process by which Soul-, Self- and God- Realization leads to the transformation of matter itself
My current understanding of Reality and Realisation as generally described is that this does not necessarily have to represent the Supreme Absolute Reality in itself, but rather the Absolute as experienced from the perspective of the inner physical, emotional, and mental being. This insight is inspired by certain comments of Sri Aurobindo (I don't recall the reference), as well as his distinction between nirvana and integral ascent-descent. I therefore place Realisation above the Three Worlds, but below the Divine Godhead region.
More: Mysticism
Transcendence Emanation Metamorphosis Evolution Divinisation
Theology = Paramology - The Study of the Absolute Reality
Note (1 Jan 2010): the following was written some years ago, and now seems to me excessively intellectual and lacking in actual experience. I find I am moving away from too much abstract mental formulation to a more fluid and intuitive approach to metaphysics. But because the following material may still be of use, I have decided to keep it
In formulating a new Metaphysical theory of Reality, there are a number of logical starting points . One can for example begin with the finite individual and explore from there, empirically, psychologically, phenomenologically, and logically, working upwards, downwards, inwards, and outwards. Or one can begin from the unitary Absolute Reality and proceed from that theological, metaphysical and ontological foundation to the world of multiplicity. Because the latter serves as the foundation of the former, I have chosen to present the Absolute first. But to begin with the relative world would be just as appropriate.
Traditionally, the study of the Absolute Reality (or Godhead or Absolute Consciousness or Enlightenment) in metaphysics falls under the rubric of Theology. However "Theology" refers more specifically to study of the God of a particular monotheistic religion (Aristotle's more philosophical use of the term would probably be better but is not widely known). And this does not apply to things like Enlightenment or Self-Realisation (e.g. when one attains states of enlightenment one doesn't see this anthropomorphic entity standing separate to oneself and to the universe). Therefore the word Paramology is here used to refer to the study of the nature of the Absolute Reality (parame - which means the the Supreme reality in Sanskrit) is used here instead . Hopefully not too clumsy neologism.
Of course, we can't really know conceptually and logically what the Absolute is, because the Absolute by its very nature transcends the mind and mental concepts; even though these mental concepts are themselves instruments of mystic teachings. The Absolute Reality, The Supreme, the Divine, the Godhead, transcends both "God" and "Void". The Reality Itself is beyond all concepts. But even though we can't understand conceptually, we can get some idea, in a Zen parable finger pointing at the moon sort of way.
Author's note (21 Dec 09) - originally I only had three levels of understanding. But that meant the page emphasised only a nonduality perspective, and hence was not integral. Therefore I have added a fourth level, to represent the Supreme experienced integrally.
The levels of Understanding
It is suggested that there are four levels of Understanding what the Absolute Reality is. These are (from the highest down) "the Supreme", "that" or "suchness", "The Absolute", and anthropomorphic "God". These correspond to the three epistemological levels of monistic mysticism - Absolute Knowing, Valid Relative Knowing, and Invalid Relative Knowing.
At the highest level, there is the Integral Absolute, the Supreme, which includes but is not limited to, positive and negative, personal and impersonal, immanent and transcendent, nondual via negatia and shunyata and I-Thou duality.
At the next highest level, relative to ordinary existence and dualistic, conceptual, consciousness, words and concepts are left behind, there is only the ineffable, "thatness" or "isness" or "suchness" (=nonduality). It can't even be called "that" because that implies something rather than something else; it can't be called the Absolute because that excludes the relative. This is the via negatia of western Theology and mysticism, the "middle way" of Madyamka Buddhsim (shunyata is not this and not its opposite), the paradox at the heart of the Zen koan. At the same time, "negative theology" itself implies only one side of the whole; nirguna requires saguna, both being recognised as partial perspectives that have to be transcended. To say that the Absolute without qualities is more real or a more accurate description than the Absolute with qualities is to miss the point entirely. This is the central limitation of the rational mind, it cannot convey or encapsulate those realities which are above and beyond it. And while words and concepts can imperfectly indicate or hint at It, they can never truely describe it.
At the middle level (episteme), words and concepts can be used to describe the Absolute Reality. And these descriptions are good as long as we don't confuse them for the Reality in Itself. Hhere we are in the realm of metaphysics and esotericism.
Now, the various mystical and esoteric traditions of the world are (apart from a few dualistic traditions like Samkhya and Gnosticism) unanimous in affirming that behind and beyond, including but also transcending, these dualities and polarities, there is the Absolute Reality in Itself. The description of the Absolute however differs, according to the religion or esoteric tecahing one consults. Vaishvanites like Chaitanya and the Hare Krishna school of Prabhupada, and Sufis like Jili, consider the Personal Godhead higher than the impersonal. In contrast, Neoplatonism, Shankara and Wilber have the Impersonal or Nonpersonal as highest. Others like Ramanuja incorporate elements of both, or, as Sri Aurobindo perceptively suggest, say the the Supreme is beyond limitations of both Personal and Impersonal.
A further distinction is to refer to an Unmanifest Absolute on the one hand, and a Manifest Absolute on the other. The former is the Nirguna (qualityless) Brahman of Vedanta, the Tao that cannot be spoken, the En Sof, the Shunyata ("void", "emptiness", "openness"), Forefather of Gnosticism, and Godhead of Dionysus and Eckhart. The latter is Saguna (with qualities) Brahman, the Logos of Philo and Sufism, the Manifest Godhead, or the Supermind of Sri Aurobindo.
At the lower level of understanding (doxa or mere opinion), the Reality in itself is completely lost and distorted by non-gnostic intellectual or religious philosophical, theological, or anthropomorphic and sectarian concepts of "God". While these may be fine and even useful as allegory and metaphor, it should not be taken literally. To do so means one is caught up with thoughtforms, and mostly outdated or limited ones at that.
Transcendence Involution/Emanation Metamorphosis Evolution Divinisation
Kheper index page
Topics index page
Metaphysics Home
Transcendence Home
Creative Commons License
Unless otherwise attributed or quoted, all text and original (self-authored) images are licensed under a
Creative Commons Attribution 3.0 Unported License
contact me
uploaded 27 May 1998; variously relocated, most recent revision 01 Jan 2010
|
__label__1
| 0.707191
|
Obesity is complex but certain factors are simple. Obese people prefer calorie-dense foods because they taste better. That’s how we become obese. That raises an interesting question. Why do the least healthy foods taste so good? Rich, sugary, fatty foods aren’t good for anyone. Yet, everybody loves them. Why is that? Aren’t our taste buds supposed to be a protective mechanism? And, of course, why do overeaters seem to like calorie-dense foods more than normal eaters? As it turns out there’s more to taste than meets the tongue. Also, what meets the tongue in normal eaters and overeaters is very different. More importantly, these differences are a key part of the obesogenic puzzle.
Origins of Taste
Taste appeared over 500 million years ago as a way of avoiding toxins and finding nutrients. All vertebrates have taste. Taste was so important to humans it changed our history; the European’s pursuit of spices launched the age of exploration.
Personal taste preferences begin before birth. In utero, amniotic fluid, which contains glucose, fructose, amino and fatty acids, is our first food. Humans also have an innate taste for sugar because newborns prefer the sweet taste of breast milk. However, maternal eating habits during pregnancy and nursing can influence children’s taste preferences. A study showed pregnant and nursing women who consumed anise, carrots, mint, vanilla, and blue cheese conveyed a taste preference for these items to their offspring. It’s basic survival. When a child begins eating solid food, eating what the mother ate is a safe bet. The taste preferences that start in the womb endure for a lifetime.
The Physiology of Taste
When I think taste, I think tongue. So let’s begin there. There are four types of papillae (filiform, fungiform, foliate, and circumvallate) that give the tongue its rough surface. The filiform papillae only determine texture, but the fungiform, foliate, and circumvallate contain five different types of taste receptors (taste buds). Each taste receptor is densely packed with taste cells, which are capped with sensors. When these sensors receive taste signals, various neural pathways swing into action, saliva production increases, and stomach secretions activate. Five taste receptors correspond with the five known tastes: sweet, sour, salty, umami, and bitter. When I read that I thought, what, there are more than five tastes left on my fingers from my last meal. However, though they are often misused interchangeably, taste, taste perception, and flavor are not the same.
Taste is a chemical process: Sweetness sensors react to sugar molecules. This relates to food with high caloric energy value. Sourness measures pH because humans have an aversion to acidic foods because they could be spoiled. Saltinessmeasures positive ions in alkali metals, in particular sodium, because of our need for mineral salt. Umami, the savory meaty taste, is detected by a receptor for glutamate. This detects protein. Bitterness is poorly defined. It may be an umbrella term for various chemical reactions that are toxic, because many dangerous compounds are bitter, although not all bitter foods are toxic.
Hot and astringent oral sensations are important, though not classified as taste or texture. When you eat a chili pepper, the capsicum molecule dissolves in your saliva. The trigeminal nerve triggers a burning sensation. This nerve also detects heat, cold, and pain. Although spicy is not classifiably a taste, it is a trigeminal sensation, like pepper, garlic, ginger, and menthol.
Taste and the Other Senses
I used to think taste was the only sense involved in enjoying food—not true. Actually, gustatory enjoyment is not taste, but taste perception. Taste perception involves taste, sight, hearing, touch, and smell. Besides taste, smell is the sense most engaged in the enjoyment of food. The olfactory epithelium detects aromas by interacting with odor molecules entering via the nose or the back of the mouth. It has millions of neurons, with specific receptors that combine odor molecules and subsequently produce an electrical impulse. This in turn transmits a signal to the olfactory bulb, then to the cortex and simultaneously to the limbic system, where human emotions and memories are stored. Also, smell is the only sensory input that is not first processed through the thalamus, the brain’s clearinghouse for sensory information. This direct connection to the limbic system is why smells can spark deep memories and very emotional responses.
Smell is also more complex than taste. We have five receptors for taste. Taste occurs when molecules bind to these five receptors on the tongue. From there, signals travel to specific brain regions. We have 350 different types of receptors that can perceive over 10,000 different odors. When odor molecules bind to nasal receptors smell occurs and goes to certain brain regions. Chewing releases volatile molecules that go from the back of the mouth to receptors in the lining of the nasal passages. Odors traveling through the back of the throat while tasting are perceived differently in the brain. When taste and smell arrive simultaneously in the insula, the insula creates flavor because taste and smell have distinct overlapping pathways in the insula. This allows us to identify the combination of sensations that lead to flavor, which bears little resemblance to actual taste. That’s why food “tastes funny” when you have a cold. The taste is not missing, but the flavor is. You can determine, sweet, sour, salty, bitter, or umami, but not the flavor. For flavor, you need smell. It is the endless possible combinations of taste and odor that create our wide variety of recognizable flavors.
Vision is also essential to taste perception. We evaluate the aesthetics of food and then determine if it looks okay to eat. EEG studies have shown, compared to low-calorie foods, calorie-dense foods cause stronger cortical activity in the bilateral insula and frontal operculum. Pleasant changes in taste were correlated with medial orbitofrontal cortex activation. Even shape can affect taste perception. In one study, after subjects completed an unrelated task involving geometric figures, the taste perception of pointed pieces of cheese was sharper than rounded pieces of cheese.
Sound also affects taste perception, e.g., the sound of a crisp apple or potato chip. Studies have shown playing crisp audio cues, while apples are being eaten, enhances their taste perception.
Touch is another marker for differentiating taste perception, e.g., a fresh juicy ripe peach compared to a mealy dry peach, or a very hard unripe peach. Nerve endings on the taste buds provide consistency and texture information about food. This is especially true of fats, e.g., the creamy feel of ice cream or the texture of a well marbled grilled steak, compared to a very lean cut. Dedicated neurons in the orbitofrontal cortex respond specifically to the texture of fat in the mouth. Feel influences taste perception in soda as well. The taste perception of flat beverages is much different than that of fully carbonated beverages.
Overeating and Decreased Taste Sensitivity
Studies have shown that the five tastes, except sour, have distinctive regional representations on the gustatory cortex. Those studies also say while bitter and sweet receptors are intermingled on the tongue they are separated by 2.5 millimeters in the brain. This could span hundreds of neurons. The brain is probably wired this way so that bitter resides in a region that drives aversion, and sweetness in an area of attraction. The important thing about this topographical segregation is that the encoding of taste signals can drive aversive and attractive behaviors. This could begin to explain why obese people are more responsive to certain foods.
Taste receptors are unique. An overpowering sweetness to one tongue may be barely detectable to another. So, differences in satiety would also differ among individuals. This is especially important to overeaters. Conceivably a person’s taste receptors could mitigate taste perception and influence food preferences, eating habits, and subsequently weight management. Obesogenesis is complex, but studies increasingly suggest that taste receptors are a major factor. Continuous studies dating back as far as the 1950’s link a decreased ability to detect sweetness with obesity. So, is it possible that it is a decreased sensitivity to sweetness that actually causes overweight people to eat more sweets than regular eaters? Diminished ability to perceive taste, and subsequently encode flavor and satiation in the brain could be one of the reasons overeaters overeat. In other words obese people are seeking the same satiety levels that all people seek, but we just have a diminished capacity for determining when those levels are achieved because of a signal breach that begins with our taste buds. So, it’s not about liking sweets more, it is about needing more sweets to achieve satiety.
Certainly, that’s theoretically possible, and according to scientists, probable. The overeater in me is ready to jump on that train—but one problem. I’m not a big sweet eater. I am a grease monkey, and not the kind that fixes your car. Like most obese people, I crave fat more than carbohydrates. “When I die, bury me deep, with a bowl of gravy at my feet, and a platter of deep fried fatty meat in my hand, and I’ll smack my way to the promised-land” has been my spiritual mantra for years. And fat isn’t even one of the basic five tastes. Hmm… looks like this train might not be coming. It’s curious all around. The tongue has receptors for two of the three mandatory macronutrients—sweet for carbohydrates, and umami for protein. It would logically conclude that humans would have some form of taste response for fat, the remaining macronutrient. While fat is not one of the basic tastes, it affects food’s taste perception, appearance, texture, and even smell. Obese people are much less sensitive at detecting fatty acids (the breakdown of fats) than people who are not overweight. This low sensitivity leads to significantly more fat consumption and subsequent weight gain. Predisposition to this can have various causes, beginning with genetics, in utero and neonatal exposure as well as signal breaches in taste sensitivity, flavor construction in the insula, and abnormalities in the orbitofrontal cortex.
So the key issues as I see them are the heavy involvement of smell with taste, and decreased sensitivity for detecting the five basic tastes, and fatty acid insensitivity, in achieving satiety. Could this be the reason normal eaters, “get enough” and I just never do when it comes to food? Also,direct communication between smell and the limbic system is a likely factor. Amygdala and hippocampal remodeling, due to adverse early life experience, has been reliably associated with obese populations. This raises the question, if the amygdal-hippocampal complex has undergone restructuring, how does this effect receiving, processing and responding to signals from the olfactory epithelium. That’s all fine and well: the train has arrived and we’re on it. Now for the important question: where is this train going, and more importantly where do we get off?
The bad news for chronic overeaters, such as myself, is that our taste detection, driving our taste perception, and subsequent eating habits is impaired and placing us in harm’s way. The good news is we can compensate for these breaches in taste detection insensitivity and change our taste perception. Stay tuned for the next post and we will explore that. Until then, remain fabulous and phenomenal.
If you enjoyed this post, please like Obesely Speaking on Facebook
Click here to be notified of new posts
Araujo, I. E. (2003). [Taste representation in the human cortex and the central control of appetite]. Rev Bras Psiquiatr, 25 Suppl 2, 25-28, 77.
Birch, L. L. (1999). Development of food preferences. Annu Rev Nutr, 19, 41-62.
Biroh, G. G., & Mylvaganam, A. R. (1976). Evidence for the proximity of sweet and bitter receptor sites. Nature, 260(5552), 632-634.
Cabanac, M., & Duclaux, R. (1970). Obesity: absence of satiety aversion to sucrose. Science, 168(3930), 496-497.
Carbohydrate taste, appetite, and obesity. (1987). Neurosci Biobehav Rev, 11(2), 131-262.
Chevrot, M., Bernard, A., Ancel, D., Buttet, M., Martin, C., Abdoul-Azize, S., et al. Obesity alters the gustatory perception of lipids in the mouse: plausible involvement of lingual CD36. J Lipid Res, 54(9), 2485-2494.
Crow, J. M. Obesity: insensitive issue. Nature, 486(7403), S12-13.
Degrace-Passilly, P., & Besnard, P. CD36 and taste of fat. Curr Opin Clin Nutr Metab Care, 15(2), 107-111.
Donaldson, L. F., Bennett, L., Baic, S., & Melichar, J. K. (2009). Taste and weight: is there a link? Am J Clin Nutr, 90(3), 800S-803S.
Frank, S., Kullmann, S., & Veit, R. Food related processes in the insular cortex. Front Hum Neurosci, 7, 499.
Gravitz, L. Food science: taste bud hackers. Nature, 486(7403), S14-15.
Grinker, J. (1978). Obesity and sweet taste. Am J Clin Nutr, 31(6), 1078-1087.
Harris, G. (2008). Development of taste and food preferences in children. Curr Opin Clin Nutr Metab Care, 11(3), 315-319.
Huang, A. L., Chen, X., Hoon, M. A., Chandrashekar, J., Guo, W., Trankner, D., et al. (2006). The cells and logic for mammalian sour taste detection. Nature, 442(7105), 934-938.
Humphries, C. Cooking: delicious science. Nature, 486(7403), S10-11.
Kane, F., & Law, M. E. (1950). Nerve connexions of taste-buds. Nature, 165(4207), 978.
Khan, M. A. (1981). Evaluation of food selection patterns and preferences. Crit Rev Food Sci Nutr, 15(2), 129-153.
Mathieu, A., Liebermeister, H., Orlik, P., & Wagner, M. W. (1976). [Differences in taste assessment of sweeteners by normal and overweight persons]. Dtsch Med Wochenschr, 101(18), 703-708.
Mela, D. J. (2001). Determinants of food choice: relationships with obesity and weight control. Obes Res, 9 Suppl 4, 249S-255S.
Nasser, J. (2001). Taste, food intake and obesity. Obes Rev, 2(4), 213-218.
Pasquet, P., Frelut, M. L., Simmen, B., Hladik, C. M., & Monneuse, M. O. (2007). Taste perception in massively obese and in non-obese adolescents. Int J Pediatr Obes, 2(4), 242-248.
Salbe, A. D., DelParigi, A., Pratley, R. E., Drewnowski, A., & Tataranni, P. A. (2004). Taste preferences and body weight changes in an obesity-prone population. Am J Clin Nutr, 79(3), 372-378.
Shepherd, G. M., Getchell, T. V., & Mistretta, C. M. (1986). Neurobiology. Questions of taste and smell. Nature, 324(6092), 17-18.
Simon, Y. (1994). [Food preferences in obesity]. Rev Med Brux, 15(4), 259-261.
Stalling, R. B., & Sobotowicz, W. (1980). Obesity, compatibility, and a taste preference. Percept Mot Skills, 51(3 Pt 1), 871-877.
Szalay, C., Aradi, M., Schwarcz, A., Orsi, G., Perlaki, G., Nemeth, L., et al. Gustatory perception alterations in obesity: an fMRI study. Brain Res, 1473, 131-140.
Thompson, D. A., Moskowitz, H. R., & Campbell, R. G. (1977). Taste and olfaction in human obesity. Physiol Behav, 19(2), 335-337.
Trivedi, B. P. Gustatory system: the finer points of taste. Nature, 486(7403), S2-3.
Trivedi, B. P. Neuroscience: hardwired for taste. Nature, 486(7403), S7-9.
Most Recent Posts from Obesely Speaking
Addicted to Romantic Suspicion
A life sentence without the possibility of love
Mind, Body and Election 2016
Our immune system is getting burned by this heated election.
Harbaugh's Coaching Genius Strikes Again
What the SEC's Harbaugh envy is really about
|
__label__1
| 0.790538
|
János Gosteli
Count of Haslau, Master of Coin in Denzegk, Patriarch of the Gosteli
“The legacy of the Red Men lives on in our blood. Who better to make true the words of the prophet? We will take what is ours, and the Novíla will run red as death one again.”
-Janos Gosteli at the Battle at Faircross
Age: 49
Ethnicity: Svalek
House: Gosteli
Other Titles: Lord of Haslau, “The Snake”
Early Years
János Gosteli was born in the Brakenvald near Moq, the second child of Viscount Alfonso Gosteli II and his wife Petra in the year 1043. Alfonso was captured 2 years later at the Battle of Lyapov River by his sworn enemy Peter Isias. To obtain his release, it was agreed that János and his brother Uberto would be sent to Burning Peaks in his place. They remained there for 2 years, until the war ended. It was noted by his tutors that János excelled in literature and the arts.
Alfonso was a skilled merchant, and expanded the previously military-rural family into successful mercantile exploits as well as banking (namely Blue Feather Mercantile), far ahead of the marshlander nobles at the time who saw mercantilism as an artisan skill. In this time, János learnt valuable skills in finance. However Alfonso wished for Uberto to take the Family trade and lands, and for János to take up the Cloth. In reality, what happened was the reverse. János quickly climbed the ladder of both the brendenburgh standing army and the Zerollean merchant’s guild, establishing with his father the Gosteli name in finance.
Around this time, Alfonso raised the young Phillip of Anjora in his household, hoping to use him to establish a dynastic claim to the house, which seemed to be almost extinct at the time. However Alfonso had no daughter to wed him to, leading to a dispute with the Anjora as to the custody of Phillip. This was one factor that led to the Gosteli-Anjora Feud. János’ refusal to trust the del Bove family in this feud led to an attempt on his life many years later.
Marriage and Warfare
János by now was in his early twenties; an icon in the court and already renowned for his financial skill, as well as his astute and perceptive nature in times of war. Having bought the Black Brothers Band, János was a key player in the arrangemed marriage between Maria Ceratis and Anthony Lugus against the wishes of the powerful Anjora family. Lugus thought highly of the young Gosteli and kept him in the courts; even promoting him to Generalisimo in order to give him the position of Strategos; preventing him from going to war. Soon afterwards János was arranged a traditional marriage with Catalina Visconti, who would bear him 2 children, Bernardo and Maria (the latter was indeed named after the famed Ceratis). Over the next few years János would consolidate power, befriending the Duke of Denzegk, placing his brother as Bishop, discovering two plots against Lugus, serving as a moqolese emissary and most notably absorbing a trade post in Paulto into Blue-Feather. The Mercantile company was largely disbanded in the later Civil War, due to Del Bove intervention.
Shortly after the birth of Maria, Catalina was killed during travel by bandits. János remarried to Anna Vettin in a hastily arranged marriage. She bore him three children: Piero, Kallisto and Clara. Around this time János settled an unknown dispute with Antonio Anisari, notable due to the result of allowing the Anisari family duty-free trading during the spring, a key factor in the Marshlander Civil War.
A few years later, János was charged with fraud by the del Bove family. Bernardo proved the family innocent via trial by combat, in which he slew Franco del Bove II in single combat.
János was a vital player in the Marshlander Civil War
A closeup of a large painting in Haslau, depicting János and his son Kallisto
With Catalina:
With Anna:
János Gosteli
From Amanne Broccoli21
|
__label__1
| 0.941389
|
We need to prepare kids for today and tomorrow, not yesterday.
As Eric Hoffer said, “In times of change learners inherit the earth; while the learned find themselves beautifully equipped to deal with a world that no longer exists.” Yet, too often our schools are set up for adults, not for the students. In fact, we typically ban the digital tools that engage kids and they use for their learning outside of schools. It is time for adults to listen to our kids and leverage the technologies they have (mobile devices, for example) for learning.
We must focus on learning…and that means bridging formal and informal.
Too often we think that learning = education. We narrowly define learning as the time spent in class. In fact, learning happens both in and outside formal classrooms, and increasingly mobile technologies enable us to bridge those environments. Educators should partner with libraries, museums, national parks and other informal learning setting and use technology to create engaging, self-paced learning environments that leverage the passions of kids.
There are exciting new ways to personalize learning and engage kids—if we leverage formative data and provide feedback to the learner.
What is a high performing learning environment? Look no further than the online game that your kid is “playing.” Rather than teaching to the average, the game moves kids as fast as they can master the content. That is precisely the kind of learning environment we should have in our classrooms—one as good as the most compelling and fun game, but one that has learning at the core. How do we get there? By providing constant feedback and formative data to the learner so we can move to faster and deeper learning.
Educators need to be less isolated and more part of a community of practice…one that is available 24x7.
Educators—be they teachers or principals—do not spend much of their professional day with their colleagues. In fact, the practice of education is typically done in isolation and behind closed doors. Yet, there are new ways to use online communities of practice (CoP) to link educational professionals and move towards continuous improvement. School systems should learn from the Online Connected Educators Project www.connectededucators.org supported by US Department of Education to learn best practice around moderating and facilitating a valuable professional resource for your faculty.
Our vision should be Participatory Learning.
Prof. Henry Jenkins argues that over the past 20 years we have moved to a more Participatory Culture where information and expertise is increasingly less hierarchical and society is more participatory. What does that mean for the kind of education we need to prepare for the world? It means that collaboration is increasingly a critical life skill. We must increasingly apply social networking/Web 2.0 tools to enable a much more participatory learning environment.
|
__label__1
| 0.929237
|
121 of 875
This is a 23 year old, 5’7”, 138 lbs woman with limited fat, whose primary concern was the shape of her buttocks. By using her fat from the abdomen, we were able to give her the curve she always wanted.
|
__label__1
| 0.790589
|
Graphene is a 2D honeycomb lattice of carbon that was first isolated in 2004. It boasts a wealth of fascinating electronic properties, many of which come from the fact that electrons in the material travel through it at extremely high speeds for relatively long distances without hitting anything. This means that electronic devices, like transistors, made from graphene could be faster than any that exist today.
The team, led by Sagar Bhandari and Robert Westervelt at Harvard, studied a sample made from a hBN−graphene−hBN sandwich with two narrow contacts along each side, separated by 2.0 µm, and large source and drain contacts at either end. Hexagonal boron nitride (hBN) is an excellent substrate for graphene, because the two materials have very similar lattice constants. The hBN-graphene-hBN sample was placed on a heavily doped Si substrate, which acts as a back-gate, covered by an insulating layer of SiO2.
Scanning gate microscopy images electron flow
Bhandari and colleagues observed the semicircular flow of electrons in graphene between the two narrow contacts when the diameter of the cyclotron orbit is equal to the contact spacing. They obtained their result by placing a scanning gate microscope (SGM) tip just above the graphene sheet. The charge on the tip creates an image charge in the conducting graphene directly below the tip that scatters the electron flow, casting a shadow “downstream”. By measuring the change in electron flow as the tip is scanned above the graphene, the researchers obtain an image of the cyclotron orbit.
“Imaging electron trajectories in this way allows us to directly see and understand how electrons move though graphene,” explains Westervelt. “The technique will be a very valuable tool for designing new ‘ballistic electronics’.”
Graphene electrons behave like quantum waves
“Although the above description treats electrons as if they were classical particles, they actually behave as quantum waves,” he says. “Indeed, we previously used scanning gate microscopy to image interference fringes for electrons in a GaAs two-dimensional electron gas, spaced by half the Fermi wavelength. We now plan to do similar experiments to image electron waves in graphene and other atomic-layer materials.
“In collaboration with Philip Kim’s group, also at Harvard, we are imaging electron flow though narrow channels and constrictions in bilayer graphene in an effort to develop quantum point contacts that are only half a wavelength wide,” he tells “We also hope to use the SGM tip to create graphene quantum dots that hold an integer number of electrons.
"By combining Kim’s team’s expertise in device design and fabrication with my group’s imaging technique, we hope to make important advances in the field of atomic layer devices," he adds.
The research is detailed in Nano Letters DOI: 10.1021/acs.nanolett.5b04609.
|
__label__1
| 0.754986
|
Copyrighting a Caesar Salad
by epicurious
on 06/29/07 at 06:05 AM
A New York Times article on a chef's lawsuit spotlighted a possible new trend: As Pete wells reported, Pearl Oyster Bar's Rebecca Charles was suing a former employee, Ed McFarland, over intellectual property rights. McFarland had worked at Charles's famed New York eatery and then over a year ago left and opened his own place, which Charles's said was strikingly similar to Pearl -- from the decor, to the menu to the recipe for a Caesar salad. She apparently is suing him on behalf of all chefs who've had the same thing done to them.
Being influenced by your mentors is not just common but the rule, and those chefs who were not flattered by their imitators were likely heavily mirroring restaurants from their own travels or experience -- everyone is influenced by someone. Thus, it's hard to know where imitation and influence end and infringement begins.
In Chicago Magazine's online "Dish" column, editor Penny Pollack asks some local chefs what they thought and as she says, "none were particularly sympathetic to Ms. Charles:"
"Look at all the people who worked under Jean Banchet [founder of the recently closed legendary Le Francais]. A lot of what we do when cooking straightforward French is stuff we learned from Jean Banchet. He could say we stole his intellectual property. But instead I think it makes him feel as though he's got a lineage. Banchet in turn learned from Fernand Point."
Michael Altenberg, executive chef/owner (Bistro Campagne, Crust)
"If I had only one good recipe in me, I don't belong in this business. And I don't see how you can copyright an aesthetic. Where do you think we got the purse stool idea [for Tru]? Alain Ducasse in Monaco was doing it. Rick [Tramonto] and I saw it on our honeymoon and knew we wanted to do it someday."
Gale Gand, executive pastry chef/partner (Tramonto's Steak & Seafood, Osteria di Tramonto, RT Lounge, Gale's Coffee Bar)
Where do you stand on this issue? Is Charles right or wrong?
Tagged with: News & Gossip
12:54:01 PM on
First of all, I don't think "copyright" was the issue. Copyrights protect written and artistic expression. Menus can be protected by copyright, but recipes can't. Nor can restaurant decor. Now, what the issue really appears to be is alleged theft of trade secrets, and infringement of trade dress. Trade secrets can be anything of value for which measures were taken to keep as a secret. I suppose that a secret method for preparing something, or a "secret formula" kind of recipe could be considered trade secrets. If a restaurant or chef really does take measures to keep some technique or recipe secret, then I see no reason why an employee should not be liable if he or she knowingly uses the trade secret elsewhere. Of course, if a recipe or technique can be determined simply from looking at a dish, tasting it, etc., then it is simply not a trade secret.
"Trade dress" is a concept rooted in trademark law. With respect to restaurant decor, the idea is that if there are distinctive elements of a restaurant's decor that the public comes to uniquely associate with that restaurant, then the restaurant should be entitled to protect them. There was a famous case involving a Mexican restaurant, where the Supreme Court found that "inherently distinctive" elements such as overhead garage doors uniquely identified that restaurant and should be protectable as the restaurant's proprietary trade dress. Again, I see nothing wrong with a restaurant pursuing a former employee who copied inherently distinctive things that the public came to understand were associated with that particular restaurant.
Yes, I'm a lawyer. And like many of us, also a foodie.
welcome to the epi-log
guest contributors
|
__label__1
| 0.84081
|
Loading the player...
What is 'Inflation'
As a result of inflation, the purchasing power of a unit of currency falls. For example, if the inflation rate is 2%, then a pack of gum that costs $1 in a given year will cost $1.02 the next year. As goods and services require more money to purchase, the implicit value of that money falls.
Historical Examples of Inflation and Hyperinflation
Today, few currencies are fully backed by gold or silver. Since most world currencies are fiat money, the money supply could increase rapidly for political reasons, resulting in inflation. The most famous example is the hyperinflation that struck the German Weimar Republic in the early 1920s. The nations that had been victorious in World War I demanded reparations from Germany, which could not be paid in German paper currency, as this was of suspect value due to government borrowing. Germany attempted to print paper notes, buy foreign currency with them, and use that to pay their debts.
This policy led to the rapid devaluation of the German mark, and with it, hyperinflation. German consumers exacerbated the cycle by trying to spend their money as fast as possible, expecting that it would be worth less and less the longer they waited. More and more money flooded the economy, and its value plummeted to the point where people would paper their walls with the practically worthless bills. Similar situations have occurred in Peru in 1990 and Zimbabwe in 2007-2008.
Inflation and the 2008 Global Recession
Inflation in Moderation: Harms and Benefits
While excessive inflation and hyperinflation have negative economic consequences, deflation's negative consequences for the economy can be just as bad or worse. Consequently, policy makers since the end of the 20th century have attempted to keep inflation steady at 2% per year. The European Central Bank has also pursued aggressive quantitative easing to counter deflation in the Eurozone, and some places have experienced negative interest rates, due to fears that deflation could take hold in the eurozone and lead to economic stagnation. Moreover, countries that are experiencing higher rates of growth can absorb higher rates of inflation. India's target is around 4%, Brazil's 4.5%.
Real World Example of Inflation
Inflation is generally measured in terms of a consumer price index (CPI), which tracks the prices of a basket of core goods and services over time. Viewed another way, this tool measures the "real"—that is, adjusted for inflation—value of earnings over time. It is important to note that the components of the CPI do not change in price at the same rates or even necessarily move the same direction. For example, the prices of secondary education and housing have been increasing much more rapidly than the prices of other goods and services; meanwhile fuel prices have risen, fallen, risen again and fallen again—each time very sharply—in the past ten years.
Inflation is one of the primary reasons that people invest in the first place. Just as the pack of gum that costs a dollar will cost $1.02 in a year, assuming 2% inflation, a savings account that was worth $1,000 would be worth $903.92 after 5 years, and $817.07 after 10 years, assuming that you earn no interest on the deposit. Stuffing cash into a mattress, or buying a tangible asset like gold, may make sense to people who live in unstable economies or who lack legal recourse. However, for those who can trust that their money will be reasonably safe if they make prudent equity or bond investments, this is arguably the way to go.
There is still risk, of course: bond issuers can default, and companies that issue stock can go under. For this reason it's important to do solid research and create a diverse portfolio. But in order to keep inflation from steadily gnawing away at your money, it's important to invest it in assets that can be reasonably be expected to yield at a greater rate than inflation.
For further reading on this subject, check out the Inflation Tutorial.
1. Inflation Protected
The types of investments that provide protection against inflation ...
2. Headline Inflation
The raw inflation figure as reported through the Consumer Price ...
3. Deflation
4. Core Inflation
A measure of inflation that excludes certain items that face ...
5. Monetary Policy
6. Zero Coupon Inflation Swap
An exchange of cash flows that allows investors to reduce or ...
Related Articles
1. Retirement
Inflation: What Is Inflation?
2. Retirement
Inflation: Conclusion
After reading this tutorial, you should have some insight into inflation and its effects. For starters, you now know that inflation isn't intrinsically good or bad. Like so many things in life, ...
3. Economics
Should You Worry About the U.S Inflation rate?
4. Economics
Inflation And Economic Recovery
5. Economics
Macroeconomics: Inflation
By Stephen Simpson Inflation is a key concept in macroeconomics, and a major concern for government policymakers, companies, workers and investors. Inflation refers to a broad increase in prices ...
6. Bonds & Fixed Income
The Money Market: A Look Back
7. Fundamental Analysis
What Causes Inflation in the United States
8. Personal Finance
Worst Hyperinflations in History
Here are the three worst episodes of hyperinflation in history. Each makes Venezuela's current inflation crisis seem modest in comparison.
9. Options & Futures
The Consumer Price Index: A Friend To Investors
10. Retirement
Inflation And Your Retirement
1. How can inflation be good for the economy?
2. What is inflation and how should it affect my investing?
3. How does inflation affect fixed-income investments?
Learn about the ways inflation can harm fixed-income investments. Find out how to monitor the impact of inflation using common ... Read Answer >>
4. What are some historic examples of hyperinflation?
Learn how skyrocketing prices can result in an economy spiraling into hyperinflation, as happened in Germany, Zimbabwe and ... Read Answer >>
5. What's the lowest year-over-year inflation rate in the history of the U.S.?
Learn about years with the lowest year-over-inflation in U.S. history. Read about how inflation is calculated using the consumer ... Read Answer >>
6. What are the key differences between stagflation and hyperinflation?
Learn the differences between stagflation and hyperinflation and the types of monetary policies used to take corrective action ... Read Answer >>
Hot Definitions
1. Demand Curve
2. Goldilocks Economy
3. White Squire
4. MACD Technical Indicator
5. Over-The-Counter - OTC
6. Quarter - Q1, Q2, Q3, Q4
Trading Center
|
__label__1
| 0.623158
|
usa world animals vocab health science math brain
Great Zimbabwe
Great Zimbabwe is the name given to the remains, sometimes referred to as the Great Zimbabwe Ruins, of an ancient Southern African city, located at in present-day Zimbabwe which was once the center of a vast empire known as the Munhumutapa Empire (also called Monomotapa Empire). This empire ruled territory now falling within the modern states of Zimbabwe (which took its name from this city) and Mozambique.
Inside of the Great Enclosure in the ruins of Great Zimbabwe.
The origin of the word Zimbabwe is not known, but there are two schools of thought. It could be short form for "ziimba remabwe", a Shona (dialect: chiKaranga) term, which means "the great or big house built of stones". A second theory is that Zimbabwe is a contracted form of "dzimba woye" which means "venerated houses," a term usually reserved for chiefs' houses or graves. Currently, Great Zimbabwe is an archeological site. The site is also modern Zimbabwe's national shrine where the Zimbabwe Bird (a national symbol of Zimbabwe) was found.
An early European explorer, Viçente Pegado, Captain of the Portuguese Garrison of Sofala, described Zimbabwe thus, in 1531:
Built consistently throughout the period from the years AD 400 to the 15th century, the ruins at Great Zimbabwe are some of the oldest and largest structures located in Sub-Saharan Africa. At its peak, estimates are that the ruins of Great Zimbabwe had as many as 18,000 inhabitants.
Hill Complex at Great Zimbabwe
Built entirely of stone (those parts that survive), the ruins span 1,800 acres (7 km2) and cover a radius of 100 to 200 miles (160 to 320 km). The ruins can be broken down into three distinct architectural groups. They are known as the Hill Complex, the Valley Complex and the famous Great Enclosure. Over 300 structures have been located so far in the Great Enclosure.
The type of stone structures found on the site give an indication of the status of the citizenry. Structures that were more elaborate were built for the kings and situated further away from the center of the city. It is thought that this was done in order to escape sleeping sickness.
What little evidence exists suggests that Great Zimbabwe also became a center for trading, with artifacts suggesting that the city formed part of a trade network extending as far as China.
Portuguese traders were the first Europeans to visit the remains of the ancient city in the early 16th century. In the 19th century, after the ruins were rediscovered by Adam Renders in 1868 and reported on by Karl Mauch in 1871, they became well known to English readers from J. Theodore Bent's season at Zimbabwe, under Rhodes' patronage. Bent, whose archaeological experience had all been in Greece and Asia Minor, stated that the ruins revealed the Phoenicians as the builders. Even after his account of the Ruined Cities of Mashonaland was published, theories as to their origin abounded, with one element in common: they could not have been built by black people; they must have some Mediterranean or Biblical connection. Mauch had favored the Queen of Sheba legend. Nowadays most archaeologists accept that Great Zimbabwe was probably built by one of the Shona-speaking peoples; the Lemba, a Shona-speaking tribe living along the border between Zimbabwe and South Africa, claim Great Zimbabwe as one of a number of stone cities they profess to have built in east Africa.
The first scientific archaeological excavations at the site were undertaken in by David Randall-MacIver in 1905-1906. During the late 1920s, Gertrude Caton-Thompson proved conclusively the site was of African origin. Since then artifacts and radiocarbon dating have proved that the oldest remains date back to the 11th century.
Some of the famous soapstone bird carvings were taken from Great Zimbabwe around 1890 and sold to Cecil Rhodes, who was intrigued and had copies made which he gave to friends. Most of the carvings have been returned to Zimbabwe, but one remains at Rhodes' old home, Groote Schuur, in Cape Town.
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Great Zimbabwe ".
|
__label__1
| 0.99893
|
“When you show up the kids are so excited to see you, it’s great. I really do believe that this program does boost the self-esteem of the children.”
Sarah, Cross-Age Mentor, Junior at Red Bluff High
School–Based Mentoring Programs
Lunch Buddies
Lunch Buddies is catered toward the working professional or busy adult who still wants to give part of his/her time to mentoring a student. Mentors serve as a positive role model and commit to spending at least one lunch hour per week for one school year with a specific student at school. Mentors do not have to provide lunch for the student, but may if they wish. They meet with their mentee in a quiet area of the school and spend one–on–one time sharing lunch and conversation. Depending on interests, they may discuss school, goals, social skills and relationships, etc. Lunch buddies are only required to commit to one lunch hour per week, but can schedule as many as time permits.
Cross–Age Mentoring
The Cross–Age program matches a college or high school student mentor with a young elementary school mentee between the ages of 5–13 who is enrolled in the SERRF After School Program. Mentors commit to meeting with mentees at for least one hour per week for the duration of a semester. Mentors assist their student mentees with homework and social skills. High school students can earn a stipend for completing the program.
The Mentor–Tutor program is similar to Cross–Age Mentoring, however it matches an adult volunteer with an elementary school student. The Mentor–Tutor program focuses on improving academic achievement and literacy skills, and includes English Language Learners. Mentors meet with their mentee after the regular school day for at least two hours per week for the duration of one semester.
|
__label__1
| 0.845077
|
This Is How I'm Eating More Vegetables
Micro Resolutions for 2016
Last month when I made my confession about the lack of daily vegetables in my diet, what felt like a failure to admit quickly became a support-group moment for me. Reader suggestions pointed me to both easy solutions and delicious adventures. Several weeks in, green things and vegetables overall are definitely making a more noticeable appearance in my diet, and I've realized that the path to a consistent diet of healthy foods is laid with both intention and preparation.
Of course, there were days when I didn't meet my goal to eat veggies for breakfast, lunch, and dinner, but there were never successive days when I failed to eat them at all. Here's what I learned.
Planning Ahead Is Key
Prepping for breakfast was a must. Having spinach and veggies consumption-ready kept me from eyeing my toddler's no-cook breakfast options or opting for yogurt with fruit, nuts, and granola. Usually, I opted for a little of both, and my morning success usually kept me encouraged to stick to a side salad at lunch, too.
Veggies Make Excellent Snacks
So many readers said snacks were their main source for a routine intake of vegetables. What a great alternative to crackers and fruit! Here are a few of my favorite ways to snack on veggies.
• Swap crackers for bell peppers when noshing on hummus.
• Keep crudités in the refrigerator for snack attacks.
• Replace the pre-dinner snack with a side salad.
Experimentation Keeps It Interesting
Dinner was where my micro-resolution got adventurous. Trying new recipes and adding vegetables in dishes that didn't call for them helped keep me on track. It felt great to end the day with something I knew was doing good for my body, instead of hitting the pillow with the shame of surrendering to pizza or yet anther turkey burger.
The limits of my husband's diet and a toddler's scrutinizing eye sometimes made it feel a little like an Iron Chef challenge (for someone who isn't a terribly adventurous cook), but I did find some successful dishes. This pesto, sausage, and Brussel sprouts dish made a few appearances. I also played around with sides like kale salad with quinoa and homemade dressing, green beans with almonds, and broccoli slaw.
Soup Is Always Good
As predicted, soups got served up for lunch, on busy weeknights, or when we cleaned out the fridge. The best part? Everyone could eat something a little different without a lot of extra fuss.
I also wanted to share a few suggestions from all of you that really helped me in my quest. Thanks, y'all, for your thoughts!
The thing that led us to eating more vegetables and fruit (such that we have lots of them in pretty much every meal) was doing a weekly shop at a farmers market before planning our weekly meals. We go there, see what looks good, and try to buy enough to provide all our fresh produce for the week. - CGlondon
I cook for two people in their 90s who give vegetables lip service, but actually eat little (if I don't get sneaky). I process purées of different vegetable mixtures to include in everything, and keep them in single-use packets in the freezer. - JoPB
I purée a bag of super greens (or just kale or spinach), pour into an ice cube tray, freeze, plonk in a zip-top bag, and keep in the freezer. One cube in a protein smoothie. Bam! Not only do I get a big handful of greens, but the smoothie also isn't as chewy as adding fresh, and my greens don't go bad. - Mrs. Armstrong
Something that really helped me was signing up for a CSA. They deliver lots of veggies; I almost stopped going to the grocery store, except to replace pantry staples. So many veggies and you know more are coming next week, so you better buckle down and eat 'em. - miniwheat
(Image credits: Emma Christensen)
|
__label__1
| 0.905533
|
House Spoilers
House Quotes
Dr. Foreman: I'm sorry. We need to remove your eye.
Apple: My eye?
House: A moment ago you thought you were dying. Blind's actually good news.
|
__label__1
| 0.99828
|
- Small Business Trends - http://smallbiztrends.com -
Didn’t You Hear Me? I Thought I Said Mush!
mush dogs cartoon business
Often, when I’m stuck for an idea, I take something odd and throw it in a business meeting: Anthropomorphic house plant, giant robot, DNA…
Then, instead of trying to come up with an idea, you’re solving a problem. What is the anthropomorphic houseplant talking about? Is the giant robot manager a good idea? What would DNA tell its employees?
Or, in this case – what might come out of a sled dog team and a sales graph?
|
__label__1
| 0.973109
|
Climate Change 2001:
Working Group II: Impacts, Adaptation and Vulnerability
Other reports in this collection Temperature
Central America shows different signs for temperature trends, according to the specific area under analysis. For example, in Costa Rica, Alfaro (1993) identifies a positive trend in daily maximum temperature. Gómez and Fernández (1996) and OCCH (1999) have identified negative trends for large areas of Costa Rica and Honduras. MARENA's (2000) analyses of time series for Nicaragua find only a small increase in mean temperature for Managua, which might be associated with growth in urbanization.
For northwestern South America, monthly mean air temperature records show a warming of 0.5-0.8°C for the last decade of the 20th century (Pabón, 1995a; Pabón et al., 1999; Quintana-Gomez, 1999). Colombia also presents increasing trends in the time series for the daily series of daily mean and minimum temperature for the past 30-40 years. Similar patterns have been observed in average monthly dew point and relative humidity (Mesa et al., 1997; Pérez et al., 1998). Coastal cities from northern Peru presented increases in air temperature since 1940, where 16 El Niño events were reported (Jaimes, 1997; SENAMHI, 1999).
Data since the beginning of the 20th century do not show a clear tendency in mean temperature in the southern cone, but there is a decrease in the thermal range. Moreover, south of 50°S there are indications of a positive tendency (Hoffman et al., 1997). However, when a shorter record is used for the analysis, Argentina and Chile show a large warming rate of 1.2-3.0°C per 100 years (Rosenblüth et al., 1997).
In south tropical Argentina, warming is observed only during the austral autumn season (Bejarán and Barros, 1998). The Argentina humid pampa, represented by Buenos Aires, presents a warming as a result of urban effects (Camilloni and Barros, 1997). Intensity and persistence of heat and cold waves present tendencies in which the sign depends on the region (Rusticucci and Vargas, 1998).
In extra-tropical west South America (Chile), surface air temperature has varied differently during the 20th century. South of approximately 45°S, temperatures have been increasing in stepwise fashion (Aceituno et al., 1993). In the area spanning about 35°S to 45°S, the most significant feature is a well-defined cooling of 1-2°C from the 1950s to the mid-1970s.
Other reports in this collection
|
__label__1
| 0.860474
|
Published on
Published in: Technology, Business
• Be the first to comment
• Be the first to like this
No Downloads
Total views
On SlideShare
From Embeds
Number of Embeds
Embeds 0
No embeds
No notes for slide
1. 1. REVIEWS The who, how and where of antigen presentation to B cells Facundo D. Batista and Naomi E. Harwood Abstract | A functional immune system depends on the appropriate activation of lymphocytes following antigen encounter. In this Review, we summarize studies that have used high-resolution imaging approaches to visualize antigen presentation to B cells in secondary lymphoid organs. These studies illustrate that encounters of B cells with antigen in these organs can be facilitated by diffusion of the antigen or by the presentation of antigen by macrophages, dendritic cells and follicular dendritic cells. We describe cell-surface molecules that might be important in mediating antigen presentation to B cells and also highlight the key role of B cells themselves in antigen transport. Data obtained from the studies discussed here highlight the predominance, importance and variety of the cell-mediated processes that are involved in presenting antigen to B cells in vivo. Total internal reflection The immune system is highly dynamic and diverse, which and present antigen in association with MHC class II fluorescence microscopy enables it to effectively protect an individual from numer- molecules, thereby recruiting specific CD4 + T-cell A microscopy method that ous potentially pathogenic encounters. Early studies that help and stimulating B-cell proliferation and dif- allows for the identification combined techniques such as electron microscopy and ferentiation15,16 (BOX 2). Although the precise factors of fluorescence within immunofluorescence yielded valuable information on that determine the fate of activated B cells currently 100–200 nm of the interface between cells and their the static location and organization of the cells of the remain unclear, B cells can differentiate along two substrate (for example, lipid immune system, and inferred their dynamic properties distinct pathways. On the one hand, B cells can dif- bilayers or glass coverslips), (for a historical perspective and references to original ferentiate to form extrafollicular plasmablasts that thereby providing a high lateral articles see REFS 1–3). However, it is necessary to consider are essential for rapid antibody production and early and axial resolution at the cell–substrate interface and the development of immune responses in terms of both protective immune responses. On the other hand, the ability to observe intracellular and intercellular interactions in the appro- activated B cells can enter germinal centres, where they nanoscale movement of priate environment and in real time4–8. Indeed, the recent can differentiate into plasma cells, which can secrete signalling molecules during development of high-resolution imaging techniques, high-affinity antibody following affinity maturation, cellular activation. including confocal microscopy, total internal reflection or memory B cells, which confer long-lasting protection fluorescence microscopy and intravital multiphoton micro- from secondary challenge with antigen17,18. scopy, has provided insights into the spatio-temporal In this Review, we discuss recent insights into the dynamics of the molecular and cellular events that sites at which B cells encounter antigen in vivo, as well underlie immune responses to pathogenic infection. One as the mechanisms by which these interactions occur example of such an insight is the molecular description (for excellent reviews that include comprehensive Lymphocyte Interaction of the immunological synapse, a structure that is com- descriptions of antigen presentation to T cells in vivo, Laboratory, Cancer Research monly associated with lymphocyte activation following see REFS 2,19–21 ). It is now clear that B cells can UK London Research the recognition of a specific antigen9–12 (BOX 1). encounter and respond to antigen through many dif- Institute, Lincoln’s Inn Fields Laboratories, 44 Lincoln’s Inn B-cell activation is initiated following engagement ferent mechanisms depending on the nature and size Fields, London WC2A 3PX, UK. of the B-cell receptor (BCR) by a specific antigen. of the antigen itself, as well as on the cellular context Correspondence to F.D.B. B cells can recognize and respond to both soluble and location in which antigen presentation occurs. e‑mail: facundo.batista@ and membrane-associated antigen, although recent This provides great versatility in terms of initiating doi:10.1038/nri2454 insights suggest that membrane-associated antigens responses that are appropriate to the particular antigen Published online are more important for B-cell activation in vivo 13,14. and are therefore the most effective for the protection 12 December 2008 Following antigenic stimulation, B cells can process of the host. nATuRE REvIEws | Immunology vOluME 9 | jAnuARy 2009 | 15 © 2009 Macmillan Publishers Limited. All rights reserved
2. 2. REVIEWS Intravital multiphoton Sites of antigen encounter slOs are extremely well connected to the blood and microscopy As cells of the immune system can respond to a huge lymphatic systems, allowing them to continually sample A microscopy method that range of potential pathogenic challenges throughout the and concentrate antigens that are circulating through- combines the advanced whole body, these responses must be tightly coordinated out the body. The importance of slOs in organizing optical techniques of laser-scanning confocal to confer effective protection. Owing to this great anti- and coordinating immune responses is evident from microscopy with genic diversity, the event of antigen encounter with an the severe impairment in the activation of naive lym- long-wavelength multiphoton antigen-specific lymphocyte that can mount a rapid and phocytes in alymphoplastic (aly/aly) mice and asplenic fluorescence excitation to appropriate response would seem unlikely. To maximize (homebox 11-deficient) mice23. Accordingly, any mean- capture high-resolution, the probability of such an interaction, these events occur ingful investigation into the spatio-temporal dynamics three-dimensional images of living cells and/or tissues that in defined sites, such as the lymph nodes and spleen, and the mechanisms by which lymphocytes encounter have been labelled with which are collectively known as secondary lymphoid antigen in vivo must be considered within such highly fluorophores. It provides a organs (slOs). These sites possess a highly organized organized environments. greater tissue imaging depth microarchitecture that is necessary for the compartmen- (up to 350 µm depending on the tissue) and less talization of numerous cellular interactions and there- Lymph nodes. It is now widely understood that photobleaching and fore provide the optimal environment for the initiation beneath the protective outer collagenous capsule, a phototoxicity than of immune responses, including the determination of lymph node is divided into three discrete (but non- conventional imaging cell fate22. Furthermore, within 24 hours lymphocytes rigid) regions that are defined by the expression of methods. that have been unsuccessful in their search for antigen specific chemokines3,24 (FIG. 1a). Directly beneath the Germinal centre recirculate throughout the body and between slOs to subcapsular sinus is a macrophage-rich sheet that sur- A highly specialized and dramatically increase the probability of encountering rounds the B-cell zone, which is also termed the cor- dynamic microenvironment cognate antigen3. tex. B cells in this region are organized into aggregates, that gives rise to secondary B-cell follicles during an immune response. It is the main site of B-cell maturation, Box 1 | The immunological synapse during which memory B cells and plasma cells that produce Lymphocyte activation is initiated following the recognition of specific antigen by clonotypic immunoreceptors, such high-affinity antibody are as the B‑cell receptor (BCR) and the T‑cell receptor (TCR). The recognition of specific antigen on a spatially constrained generated. surface is associated with membrane reorganization that results in the formation of an immunological synapse9–12. The structure of the mature immunological synapse is characterized by the spatial segregation of immunoreceptors into Plasma cell a central supramolecular activation cluster (cSMAC) from the surrounding peripheral SMAC (pSMAC), which contains integrins, A non-dividing, terminally such as lymphocyte function‑associated antigen 1 (LFA1) (see the figure). The early molecular events that underlie the formation differentiated, antibody- of the immunological synapse have been revealed by high‑resolution imaging techniques and are highly coordinated and tightly secreting cell of the B-cell regulated. Following the recognition of specific antigen and before the formation of the immunological synapse, B cells rapidly lineage. spread over the antigen‑containing surface in a manner that is dependent on intracellular signalling and cytoskeletal Memory B cell rearrangements120. During B‑cell spreading, antigen–BCR microclusters are continually assembled at the periphery of the An antigen-experienced B cell contact area between the cells14. As similar microclusters are crucial for sustained signalling in T cells121–123, we have proposed that expresses high-affinity that these microclusters form functional signalling units that are common to both types of lymphocyte14. antibodies and quickly A comprehensive genetic dissection of the requirements for B‑cell spreading identified an important role for the sequential differentiates into a plasma recruitment of the kinases LYN and spleen tyrosine kinase (SYK) to antigen–BCR microclusters in the initiation of cell during antigen-recall BCR‑induced signalling124. Furthermore, this study visualized the formation of microsignalosomes through the recruitment of responses. signalling molecules and adaptors to the antigen–BCR microclusters and showed the importance of cooperation between VAV and phospholipase Cγ2 in mediating the spreading response. The role of LYN and SYK in the initiation of BCR signalling Alymphoplastic (aly/aly) has been further supported through mice B-cell contact area with APC Antigen–BCR microcluster: side view fluorescence resonance energy transfer Mice that are characterized (APC not shown) CR APC (FRET)‑based assays125. B‑cell spreading by the absence of lymph FcR nodes and Peyer’s patches. facilitates the propagation of signalling Alymphoplasia is caused by a Antigen through microclusters by allowing the BCR spontaneous mutation in the C3 Antibody to engage more antigen, which promotes gene that encodes nuclear- fragment further localized signalling and cytoskeleton factor-κB-inducing kinase. rearrangements120. The spreading response BCR Mature immunological synapse: is followed by a prolonged contraction top view Microsignalosome phase, which results in the accumulation B cell of antigen–BCR microclusters in the cSMAC of the mature immunological Immunological synapse: side view synapse. The cSMAC functions as a site for APC internalization of antigen12,120, before it is processed and presented in association pSMAC cSMAC with MHC class II molecules; presentation Integrin receptor of antigen–MHC molecules mediates the B-cell contact area recruitment of the CD4+ T‑cell help that is necessary for full B‑cell activation15,16. APC, antigen‑presenting cell; C3, complement component 3; CR, complement receptor; cSMAC pSMAC B cell FcR, Fc receptor. Nature Reviews | Immunology 16 | jAnuARy 2009 | vOluME 9 © 2009 Macmillan Publishers Limited. All rights reserved
3. 3. REVIEWS T-cell-dependent antigen known as follicles, and are the largest population of The medulla, which is the innermost area of the A protein antigen that needs to IgMmedIgDhiCD21medCD23hi B cells in the body. Follicles lymph node, contains both B and T cells that are organ- be recognized by T helper cells are also rich in radiation-resistant follicular dendritic ized into medullary cords and is also rich in DCs and (in the context of MHC cells (FDCs) that express high levels of the adhesion macrophages. molecules) and requires cooperation between these molecules vascular cell-adhesion molecule 1 (vCAM1) lymph nodes are strategically positioned at branches antigen-specific T cells and and intercellular adhesion molecule 1 (ICAM1), as well throughout the lymphatic system to enable extensive B cells for a specific antibody as complement and Fc receptors25–28. FDCs are thought antigenic sampling of lymphatic fluid4. lymphatic fluid, response to be generated. to be of mesenchymal origin and thus form a popu- which contains various chemokines and antigens that lation of cells that is distinct from classic DCs 29. The have been collected from the body, enters the lymph Affinity maturation A process whereby the precise mechanism of FDC development is not yet node through the afferent lymph vessel and is subse- mutation of antibody fully understood, but is known to require the expres- quently filtered by the lymph node as it flows towards variable-region genes followed sion of various chemokine receptors and the presence the efferent lymph vessel. lymphatic fluid is prevented by selection for higher-affinity of B cells17,30. Following exposure to antigen, follicles from freely diffusing into the interior when it enters variants in the germinal centre leads to an increase in average may also contain specialized structures, known as the lymph node by the subcapsular sinus; instead, it antibody affinity for an antigen germinal centres, which consist of rapidly proliferat- travels to the medulla through structures known as as an immune response ing B cells within a network of FDCs. The formation trabecular sinuses. In addition, components of lym- progresses. The selection is of germinal centres is important during the develop- phatic fluid that have a molecular weight of below thought to be a competitive ment of humoral immune responses to T-cell-dependent ~70 kDa (equivalent to a dynamic radius of ~5.5 nm) process in which B cells compete with free antibody antigens, as they serve as sites for affinity maturation and the are allowed to move towards the HEv through the intri- to capture decreasing amounts generation of long-lasting memory B cells. cate meshwork of fibroblastic reticular cell (FRC)-lined of antigen. The T-cell zone, or paracortex, which is adjacent to collagenous conduits that are associated with DCs32,33 the follicles, contains high endothelial venules (HEvs) (FIG. 1b). Accordingly, early observations indicated that µ mt−/− mice A strain of mutant mice that and numerous antigen-presenting cells. The HEvs are the paracortex did not contain unprocessed antigen, carry a stop codon in the first specialized capillaries that continually supply the lymph although some antigen could be detected in DCs34. The membrane exon of the µ-chain node with and drain it of lymphocytes from and to the lymphatic fluid that exits the lymph node is enriched constant region. They lack periphery. Furthermore, HEvs in the paracortex can often with lymphocytes35 and therefore provides a means for IgM+ B cells, and B-cell mediate the recruitment of cells other than lymphocytes, these cells to return to the circulation24. development is arrested before the differentiation stage at such as antigen-presenting cells that have accumulated which IgD can be expressed. antigen in the periphery. The paracortex also contains Spleen. The organization of the lymphoid tissue of the a network of collagenous conduit fibres that allow the spleen is similar to that of the lymph node, with B-cell passage of low-molecular-mass components of lymphatic follicles and T-cell zones that contain networks of retic- fluid, including chemokines, from the subcapsular sinus ular cells (also known as the periarteriolar lymphoid to HEvs (reviewed in REF. 31). sheath) and a similar conduit system36 in the splenic Box 2 | B cells mediate antigen presentation to antigen-specific T cells B cells can have a role in initiating T‑cell responses by functioning as antigen‑presenting cells (APCs). When compared with dendritic cells, B cells are relatively poor APCs, and therefore the importance of B cells in antigen presentation to T cells has been controversial. However, their presentation potential can be enhanced following specific recognition of antigen126. Furthermore, it has been recently shown that reconstitution of chimeric µ mt–/– mice with B cells that lack MHC class II molecules results in impairment of T‑cell responses following antigen stimulation127, which suggests that presentation of antigen by B cells does contribute to T‑cell activation. Tracking and intravital microscopy of antigen‑specific lymphocytes in lymph nodes (see the figure) showed that around 24 hours following antigen encounter, B cells (green) migrated towards the B‑cell–T‑cell boundary at the edge of the follicles70 in a CC‑chemokine receptor‑7‑dependent manner48. When they reached this boundary, B cells were found to engage antigen‑specific T cells (red) for up to 1 hour. A similar migration pattern to the B‑cell–T‑cell boundary was observed in response to stimulation with particulate antigen or immune complexes following their accumulation at the subcapsular sinus (SCS)64,67. B‑cell–T‑cell conjugates are suprisingly motile and migrate through the lymph node at the same rate as unconjugated B cells. The importance of these long‑lived B‑cell–T‑cell Follicle conjugates in the generation of sustained immunity has recently been highlighted through the investigation SCS of mice that are deficient in SLAM‑associated protein (SAP)128. Although the CD4+ T cells from SAP‑deficient mice exhibit typical dendritic‑cell‑mediated activation, they cannot interact with cognate B cells, resulting in severely impaired formation and function of germinal centres. Thus, it seems that although the number of naive antigen‑specific B cells in vivo is T-cell probably low, this mechanism of antigen presentation zone to T cells by B cells contributes to the initiation of T‑cell responses in vivo. Follicle Nature Reviews | Immunology nATuRE REvIEws | Immunology vOluME 9 | jAnuARy 2009 | 17 © 2009 Macmillan Publishers Limited. All rights reserved
4. 4. REVIEWS a Lymph node Spleen Afferent lymph Red pulp Trabecular sinus Paracortex White Subcapsular pulp sinus Follicle HEV Marginal zone Medulla Marginal Efferent sinus lymph PALS Blood Central Conduit network arteriole Conduit network Follicle Arteriole branch b Conduit network c SCS Follicle T-cell zone Collagen bundles FRC Associated DC Follicle Figure 1 | The organization of secondary lymphoid organs. a | A schematic representation of secondary lymphoid organs (SLOs). The lymph node is organized into three discrete (but non-rigid) regions: the medulla, the paracortex (also known as the T-cell zone) and the follicles (also known as the B-cell zone). Antigen-laden lymphatic fluid flows from the afferent lymph vessel Nature Reviews | Immunology into the subcapsular sinus and through the trabecular sinuses to the medulla, where it exits through the efferent lymph vessel. Lymphatic fluid also flows through the conduit network in the paracortex, allowing passage of low-molecular-mass components, including chemokines and antigen, from the subcapsular sinus to high endothelial venules (HEVs). HEVs in the paracortex also allow for the entry and exit of lymphocytes to and from the lymph node. The white pulp of the spleen consists of the paracortex (also known as the periarteriolar lymphoid sheath; PALS), B-cell follicles, a central arteriole and the marginal zone. Blood arrives at the spleen at the marginal sinus through branches of the central arteriole and from there it flows to the red pulp through the marginal zone or to the white pulp through the conduit network. b | The conduit network in the lymph node is composed of a collagen core and is lined with fibroblastic reticular cells (FRCs). Dendritic cells (DCs) are often associated with FRCs and can extend short protrusions into the conduits, possibly to sample the lymphatic fluid that is transported through this network. c | A snapshot of a video generated using multiphoton microscopy on the popliteal lymph node. The distribution of seminaphtho-rhodafluor (SNARF)-labelled B cells (red) within the follicles (delineated by a dashed line) beneath the subcapsular sinus (SCS; solid line) and of carboxyfluorescein diacetate succinimidyl ester (CFSE)-labelled T cells (green) in the paracortex is shown in the absence of antigen. Scale bar represents 100 µm. white pulp37 (FIG. 1a). The spleen also contains red pulp, These marginal-zone B cells form a population of cells which is richly supplied with blood and contains various that is distinct from follicular B cells, a large propor- antigen-presenting cells, lymphocytes and plasma cells38. tion of which are polyreactive clones. Marginal-zone The outer limit of the white pulp is separated from the B cells have an IgMhiIgDlowCD21hiCD23low phenotype red pulp by a region known as the marginal zone 39. and are thought to participate in the development of This area has extensive vasculature, and blood that early immune responses to both T-cell-dependent and enters the spleen through follicular arteriole branches T-cell-independent antigens42. In contrast to lymph nodes, in the marginal sinus reaches the marginal zone before the spleen is not supplied with afferent lymphatic fluid T-cell-independent antigen its permeation through the red pulp40. The marginal (although it does contain efferent lymphatics); instead, An antigen that directly zone also contains numerous macrophages and DCs, it is specialized in mounting immune responses to activates B cells. and a sizable population of non-recirculating B cells41. blood-borne antigens43. 18 | jAnuARy 2009 | vOluME 9 © 2009 Macmillan Publishers Limited. All rights reserved
5. 5. REVIEWS Lymphocyte behaviour in ‘resting’ SLOs diffusion of antigen into the lymphoid tissue; how- To establish the sites and mechanisms of antigen encoun- ever, these encounters are usually mediated through ter with lymphocytes in vivo, it is important to understand macrophages, DCs and FDCs (FIG. 2). the localization and dynamics of these cells in the resting lymphoid organs. Although information on cell dynam- Encountering of soluble antigen. Antigen can be rap- ics in the past was inferred from studies using static idly supplied to the lymph node through the afferent approaches1–3, initial groundbreaking studies that directly lymph vessels. Indeed, antigen arrival at the subcapsu- visualized the spatio-temporal dynamics of lymphocytes lar sinus can be detected within minutes of subcutane- in vivo were possible because of advances in the field of ous administration51. As most B cells are mainly located multiphoton microscopy (reviewed in REFS 5,19). This in the follicles, lymph-borne antigens must gain access method allows for the investigation of cellular behaviour to follicular B cells in a manner that is independent in real time and to a depth in living tissue that is prohib- of the conduit system, which is present predominantly in ited by techniques such as confocal microscopy 5. The ear- the paracortex. liest multiphoton microscopy investigations were carried Interestingly, several electron microscopy stud- out on explanted or isolated lymph nodes44–46, and many ies have identified pores of ~0.1–1 µm diameter in the of the original observations have since been confirmed in regions of the subcapsular sinus that are adjacent to lymph nodes in vivo following minimal surgical disrup- the lymph-node parenchyma52–54. These pores might tion. However, high-resolution imaging of lymphocyte allow small soluble antigen, such as low-molecular-mass behaviour in splenic tissue is hampered by the technical toxins, that enter the lymph node through the afferent challenges that are associated with the isolation of this lymph vessel to directly pass into the follicle and gain vital and deeply embedded organ6. access to B cells55 (FIG. 2a). Indeed, using immunohisto- The first surprising observation from these multi- chemistry of frozen lymph-node sections, it was shown photon microscopy studies was the highly motile nature that this rapid diffusion of antigen was independent of of lymphocytes within the resting lymph node45–48. B and DCs and did not require migration of B cells from their T cells that were highly polarized in shape were found follicular location. These observations are consistent to move within their restricted cellular zones (FIG. 1c) with a previous study, which showed that immuniza- but along apparently random trajectories, with average tion of mice with soluble antigen initially resulted in a velocities of around 6 µm (for B cells) and 12 µm (for T substantial decrease in the motility of antigen-specific cells) per minute. Closer inspection of this movement fol- B cells in the follicle48. Furthermore, in the 24 hours lowing the visualization of the conduit network provided following immunization these B cells were shown to evidence for an order to this process. using an elegant present antigen in association with MHC class II mol- system involving chimeric mice that express green fluo- ecules on their surface (BOX 2) and to migrate towards rescent protein, Bajénoff et al.49 could visualize the FDCs the boundary between the follicle and the paracortex. and FRCs in the lymph node before the introduction of a Therefore, small low-molecular-mass antigens may gain population of labelled lymphocytes. This study showed access to cells in the follicles without requiring cell- that the T cells in the paracortex are in close association mediated presentation, through direct diffusion from with FRCs, which allows the T cells to be guided along pores in the subcapsular sinus. However the existence a defined network. As B cells enter the lymph node of these pores remains controversial, as they may simply through HEvs in the paracortex, it was also suggested be sites generated by cells that have recently migrated that these cells could migrate along FRCs in this area through the sinus wall. Furthermore, there is a discrep- before migrating in a chemokine-directed manner to the ancy between the dimensions of the observed pores follicles, where a similar network composed of FDCs can and the radius of the antigens that have been excluded be used to orchestrate their movement. such rapid move- from accessing the follicle by diffusion. In view of this, it ment across these networks suggests that lymphocytes in seems reasonable to postulate the existence of an alter- the lymph node are continually scanning their environ- native means of mediating the movement of smaller ment and are ready to respond to antigen as soon as it antigens into the follicles, perhaps in a manner that is is encountered. Interestingly, similar investigations have reminiscent of diffusion from the conduit system, as offered insight into the behaviour of CD11c+ DCs in the observed in the paracortex. paracortex 50. In contrast to lymphocytes, and as expected given their potential role in structural support of the con- Macrophage-mediated presentation. Although diffu- duit network, these DCs were found to be sessile, show- sion of antigen from the subcapsular sinus provides one ing movement at a velocity of less than 2 µm per minute. mechanism for exposing follicular B cells to small soluble However, this restriction in motility did not prevent the antigens, the access of larger particulate antigens to B cells rapid movement of their dendritic processes, indicating in the follicle is limited. It was therefore suggested that that these DCs retain the capacity to sample and respond specialized cells, possibly located in the subcapsular sinus, to environmental signals. might transport large antigens to the B-cell follicles53,56–58. Early microscopy studies revealed a population of macro- Presentation of antigen to B cells phages that reside directly beneath the subcapsular B cells can promptly detect and mount responses sinus52,53 and can extend their processes through it to gain to antigen after immunization. In the case of small soluble access to afferent lymphatic fluid53,56,58. As these macro- antigens, responses can be mounted following a simple phages have been shown to bind a soluble recombinant nATuRE REvIEws | Immunology vOluME 9 | jAnuARy 2009 | 19 © 2009 Macmillan Publishers Limited. All rights reserved
6. 6. REVIEWS a Afferent lymph vessel Antigen C3 fragment Antibody Subcapsular sinus Immune MAC1 complex DC-SIGN FcR SCS macrophage BCR Small soluble antigen CR Antigen-specific Follicular B cell dendritic cell Primary follicle b c SCS Antigen-specific Paracortex B cell HEV Recently migrated DC FRC Resident DC Antigen-specific B cells Antigen non-specific B cells T cell Antigen Figure 2 | B-cell encounters with specific antigen in the lymph node. a | B cells in follicles have been found to encounter small soluble antigens from the lymphatic fluid as they diffuse from the subcapsular sinus (SCS) to the follicles55. Large antigens, immune complexes and viruses can be presented to follicular B cells at the macrophage- rich SCS64,67,68. In addition, follicular B cells may recognize antigen that is presented on the surface of follicular dendritic Nature Reviews | Immunology cells (FDCs). b | Snapshot of a video that was generated using multiphoton intravital microscopy on the popliteal lymph node. The solid line identifies the position of the SCS. A magnified view of antigen–B-cell conjugates is shown, in which conjugates appear yellow as a result of the merge of the red antigen-specific B cells and green antigen (P. Barral and F. B., unpublished observations). c | Schematic view of the paracortex to illustrate where antigen-specific B cells encounter antigen at this site. B cells entering the lymph node can encounter unprocessed antigen on the surface of resident or recently migrated DCs, in close proximity to the high-endothelial venules (HEVs)73,77–79. The conduit system, which is lined with FRCs and DCs, transports low-molecular-mass components of the lymphatic fluid through the lymph node; B cells and T cells have been shown to migrate in association with the FRC network49. BCR, B-cell receptor; C3, complement component 3; CR, complement receptor; DC-SIGN, DC-specific ICAM3-grabbing non-integrin; FcR, Fc receptor; ICAM3, intercellular adhesion molecule 3; MAC1, macrophage receptor 1. Metallophilic macrophage protein that contains domains of the mannose receptor, intact antigen on their cell surface 56,58. Indeed, these A macrophage that is located it has been suggested that they may capture and concen- macrophages have been shown to capture and retain at the border of the white pulp trate antigen in a similar way to metallophilic macrophages antigen for up to 72 hours following the initial antigen and the marginal zone of the that reside in the splenic marginal zone59–61. exposure62. However, whether this involves the simple spleen. These macrophages express high levels of CD169 The macrophages in the subcapsular sinus are a dis- retention of antigen on the macrophage surface or anti- but lack expression of the tinct population to those in the medulla and have lim- gen internalization into non-degradative intracellular mannose receptor. ited phagocytic activity, which enables them to present compartments before it is recycled to the cell surface 20 | jAnuARy 2009 | vOluME 9 © 2009 Macmillan Publishers Limited. All rights reserved
7. 7. REVIEWS Table 1 | Cell-surface molecules that are implicated in presenting antigen to B cells Presenting cell Receptor Antigen presented Presentation strategy Macrophage MAC1 Complement-coated antigen Remains on the cell surface FcγRIIB IgG-coated antigen Internalized in neutral endosomes and recycled? DC-SIGN Carbohydrate-containing antigen Internalized in neutral endosomes and recycled? DC FcγRIIB IgG-coated antigen Internalized in neutral endosomes and recycled? DC-SIGN Carbohydrate-containing antigen Internalized in neutral endosomes and recycled? FDC CR1 and CR2 Complement-coated antigen Remains on the cell surface FcγRIIB IgG-coated antigen Internalized in neutral endosomes and recycled? Marginal-zone CR1 and CR2 Complement-coated antigen Remains on the cell surface B cell Follicular B cell CR1 and CR2 Complement-coated antigen Remains on the cell surface FcγRIIB IgG-coated antigen Internalized in neutral endosomes and recycled? CR, complement receptor; DC, dendritic cell; DC-SIGN, DC-specific ICAM3-grabbing non-integrin; FcγRIIB, low-affinity Fc receptor for IgG; FDC, follicular DC; ICAM3, intercellular adhesion molecule 3; MAC1, macrophage receptor 1. is not clear. In addition, macrophages are known to this virus68. Furthermore, as the retention of antigen was express a wide range of cell-surface receptors that not impaired following the depletion of C3, complement- could participate in the presentation of unprocessed independent mechanisms might also contribute to the antigen, including complement receptors, pattern- maintenance of antigen on the macrophage surface68. recognition receptors and/or carbohydrate-binding The accumulated antigen is subsequently presented scavenger receptors63 (TABLE 1). Indeed, macrophage in its intact form by macrophages for recognition by receptor 1 (MAC1; also known as αMβ2 integrin neighbouring follicular B cells. Accordingly, following and CD11b–CD18 dimer), which is a receptor for administration of antigen, it was shown that antigen- complement component 3 (C3) that is expressed by specific B cells in the follicle exhibited reduced migration macrophages, has been suggested to contribute to the over time and made stable contacts with macrophages retention of antigen on the cell surface64. Alternatively, in the subcapsular sinus64,67,68. As ICAM1 and vCAM1 the inhibitory low-affinity receptor for IgG (FcγRIIB) are expressed in the subcapsular sinus68, it is expected might mediate the internalization and recycling of IgG- that they may facilitate B-cell adhesion in this region and containing immune complexes to the macrophage cell thereby lower the threshold of antigen that is required surface, as has been shown in DCs65. Finally, the C-type for B-cell activation13,69. Together, these studies provide lectin DC-specific ICAM3-grabbing non-integrin the first clear demonstration of a role for macrophages (DC-sIGn; also known as CD209) could participate in the initiation of follicular B-cell responses. The macro- in the retention of glycosylated antigens, which is con- phage–B-cell interactions at the subcapsular sinus allow sistent with the observation that mice deficient in the antigen-specific B cells to acquire and internalize antigen mouse homologue of DC-sIGn, sIGnR1, fail to mount through their BCR before their migration to the B-cell– humoral immune responses following infection with T-cell boundary 67, where they may receive specific T-cell Streptococcus pneumoniae66. help48,70 (BOX 2). Interestingly, it has recently been noted A crucial and newly described role for subcapsular- that the response of B cells and CD4+ T cells to large viral sinus macrophages in the presentation of antigen to particles is deterministically linked to their antigen spe- follicular B cells has been recently established by three cificities71, suggesting that antigen uptake by the B cell independent studies64,67,68. These studies identified that, may not involve internalization of whole viral pathogens soon after antigen administration, subcapsular-sinus at the subcapsular sinus. macrophages are responsible for the rapid accumula- tion of various larger antigens, such as those found in DC-mediated presentation. B cells enter the lymph node immune complexes (with antibody and/or complement through the HEvs, so the paracortex would seem the ideal fragments), particulates, bacteria and viruses (FIG. 2a,b). site for the immediate presentation of antigen to these These macrophages might favour the retention of anti- cells. Furthermore, this region contains both resident DCs gen on their surface through their expression of sul- in close association with FRCs and recently migrated phated glycoproteins, such as CD169, and the lack of DCs that have collected antigen from peripheral tis- expression of the mannose receptor, which is usually sues. DCs are widely considered to be the most efficient Clodronate-loaded liposome associated with phagocytosis of opsonized antigen68. professional antigen-presenting cells and therefore are A liposome that contains the Depletion of macrophages, including those in the sub- particularly important for the presentation of peptides drug dichloromethylene capsular sinus and the medulla, through treatment with in a complex with MHC molecules to naive T cells72–74. diphosphonate. These clodronate-loaded liposomes rendered mice unable to However, B cells recognize antigen in its unprocessed liposomes are ingested by macrophages, resulting in capture and retain vesicular stomatitis virus at the sub- native state, and consequently presentation to B cells cell death. capsular sinus, resulting in systemic dissemination of would necessitate a mechanism whereby DC-accumulated nATuRE REvIEws | Immunology vOluME 9 | jAnuARy 2009 | 21 © 2009 Macmillan Publishers Limited. All rights reserved
8. 8. REVIEWS antigen is either stably displayed on the cell surface or is FDC-mediated presentation. Classically, FDCs have resistant to intracellular degradation65,75 (TABLE 1). Indeed, been considered to be the cells that are mainly respon- it has been shown that FcγRIIB can mediate the intern- sible for antigen presentation to B cells in slOs. Early alization of antigen-containing immune complexes into autoradiography analysis combined with high-resolution non-degradative intracellular compartments65, and it electron microscopy showed that extracellular antigen in has also been suggested that DC-sIGn might allow the a plasma-membrane-associated form is retained in the accumulation of intact antigen in neutral endosomes in follicles for prolonged periods after immunization51,84. DCs. Concomitant with this hypothesis, sIGnR1 has subsequently, it was established that FDCs in the fol- been implicated in the internalization of HIv-1 into a licles are responsible for mediating the retention of anti- non-lysosomal compartment of DCs and the subsequent gen in the form of immune complexes26,85,86. In addition delivery of intact HIv-1 virions to slOs76. to their role in antigen retention and presentation, it is A population of DCs in the paracortex that can known that FDCs function as potent accessory cells dur- present intact antigen to B cells has been identified77–79. ing B-cell activation, possibly through mechanisms that A detailed characterization of this DC population by involve the secretion of chemokines and/or the expres- intravital multiphoton microscopy showed that these sion of FcγRIIB87. cells are mainly located around HEvs so that migrat- The distinctive phenotype of FDCs supports the ing B cells can survey their antigenic contents79 (FIG. 2c). retention of immune complexes in the follicles through Following the administration of antigen-loaded DCs two different mechanisms (TABLE 1). The first mechanism to mice, recently migrated antigen-specific B cells depends on the complement system85,88,89. FDCs express show decreased motility and an increase in their resi- high levels of complement receptor 1 (CR1) and CR2 dency time on DCs. Interestingly, these DCs retained (also known as CD35 and CD21, respectively), which the capacity to stimulate B cells following treatment bind to various fragments of C3. Chimeric mice that lack with pronase (a mixture of proteinases) to remove cell- expression of CR1 and CR2 in the radioresistant stromal- surface-exposed antigen, suggesting that DCs can inter- cell compartment (including FDCs) cannot deposit nalize and then recycle intact antigen to their cell surface. antigen on the surface of FDCs90,91, and FDCs from mice The DC-mediated presentation of antigen to B cells that are unable to produce CR2 ligands cannot present in the paracortex is the ideal environment in which to antigen to B cells92. receive the necessary T-cell help for their maximal acti- The second mechanism of antigen deposition involves vation79. In support of this, DCs, B cells and T cells have the retention of immune complexes that contain IgG fol- been shown to colocalize in this region of the lymph lowing their binding to Fc receptors, such as FcγRIIB, node50. This DC-mediated activation of B cells may that are expressed on the surface of FDCs in germinal give rise to extrafollicular plasma cells that mount early centres28,93. Consistent with this, FcγRIIB-deficient mice antibody responses to antigen. Alternatively, following show severely reduced trapping of immune complexes in activation by CD4+ T cells, B cells might migrate to the the lymph node and spleen, and FcγRIIB-deficient mice follicle and mediate germinal-centre formation. It will that were reconstituted with wild-type, antigen-specific also prove valuable to characterize the in vivo dynamics lymphocytes exhibit severely impaired recall responses of a population of mannose-receptor-binding DCs that to immune complexes28. accumulate soluble antigen in the follicles and present it Deposition of antigen on the surface of FDCs through Endosome to follicular B cells80. either or both of these mechanisms would therefore be A vacuolar compartment Technical constraints have limited the application expected to increase the initiation of immune responses. where large molecules are transported after being of intravital multiphoton microscopy in the study of Indeed, preformed immune complexes58,94 and antigen engulfed by endocytosis. The lymphocyte dynamics in the spleen. However, as the con- coated with C3d fragments95 are both associated with the endosome can then mature duit system in the white pulp36 and the core organization stimulation of B-cell activation, potentially as a result of and fuse with lysosomes, which of B- and T-cell zones in the spleen are similar to those increased deposition of antigen on the surface of FDCs96. contain degrading enzymes. in the lymph node, the mechanisms of antigen presen- Furthermore, following their binding to antigen, natural Endosomal and phagosomal pathways are interconnected. tation to B cells might be similar in both tissues. The IgM antibodies that are produced mainly by peritoneal splenic marginal-zone B-cell population has been shown B-1 cells97 induce the formation of immune complexes B-1 cell to rapidly produce antibody in response to blood-borne and accelerate the deposition of antigen on the surface An IgMhiIgDlowMAC1+ antigen, and therefore these cells have an important role of FDCs27. Mice with a targeted deletion in the carboxy- B220lowCD23– cell that is dominant in the peritoneal and in the initiation of early immune responses81. However, terminal tail of IgM fail to express serum IgM and show pleural cavities. B-1-precursor the participation of marginal-zone B cells at later stages delayed humoral immune responses, suggesting a role cells develop in the fetal liver of the immune response has been less well character- for FDCs in the initiation of immune responses98,99. and omentum, and in adult ized. static in vitro imaging approaches have been used Despite the ability of FDCs to present unprocessed mice the size of the B-1-cell to study DC-mediated antigen presentation to splenic antigen, the importance of this pathway for the activation population is kept constant owing to the self-renewing marginal-zone B cells82 and have shown that this activa- of naive B cells during the initiation of primary immune capacity of these cells. B-1 tion leads to the rapid generation of plasma cells that responses, as well as its underlying mechanism, have yet cells recognize self produce IgM independently of T-cell help, allowing for to be firmly established. Interestingly, it has been postu- components, as well as the rapid and enhanced formation of antigen-containing lated that FDCs may be particularly important for the common bacterial antigens, and they secrete antibodies immune complexes. Intriguingly, a population of B cells presentation of microbial antigens, in response to which that tend to have low affinity with similar characteristics to marginal-zone B cells has pre-existing natural IgM antibodies could facilitate the and broad specificity. been detected in human lymph nodes83. rapid formation of immune complexes, thereby resulting 22 | jAnuARy 2009 | vOluME 9 © 2009 Macmillan Publishers Limited. All rights reserved
9. 9. REVIEWS in microbial-antigen presentation by Fc receptors on the to antigen retention, FDCs might have another role surface of FDCs100. However, it is known that FDCs in during affinity maturation109. However, these studies primary follicles do not express high levels of FcγRIIB28 did not exclude the possibility that competition among and therefore this receptor cannot have an important B cells for antigen could have a role in the selection of role in antigen retention and presentation during the high-affinity B-cell clones in the germinal centre. In initiation of immune responses. view of this, it would prove extremely informative to FDCs can also act as antigen ‘depots’ in the slOs characterize the spatio-temporal dynamics of cells that such that they can present antigen even after the initial retain antigen within immune complexes, which would ‘wave’ of antigen has passed26–28,101. This is important establish the precise role of deposits of antigen on FDCs for the development of an effective and long-lasting during the process of affinity maturation. immune response, as the initial encounter of antigen with naive B cells in the slOs is likely to be of low How does antigen gain access to FDCs? As a consequence affinity. under these conditions, activated B cells then of the role of FDCs in mediating antigen presentation to enter germinal centres, where they undergo affinity B cells, much effort has been invested in addressing the maturation17. This process allows the selection of B-cell apparent anomaly of how antigen in the form of immune clones with higher affinity for antigen during a T-cell- complexes can gain rapid access to FDCs, which are con- dependent antibody response and starts a few days after fined to the B-cell follicles. As the subcapsular sinus and the initiation of the response. the conduit system restrict the diffusion of large antigens The classic model that described the mechanism of from the lymphatic fluid, a cell-mediated mechanism antigen presentation to B cells in germinal centres was must operate to transport antigen to FDCs. based on several biochemical and histological observa- In the spleen, marginal-zone B cells have been impli- tions. In this model, the germinal centre was divided cated in this process59,110 (FIG. 3a). The location of B cells into two functionally distinct zones17. The dark zone in the marginal zone makes them ideally positioned was thought to contain centroblasts and to be the site to sample and mount rapid responses to blood-borne of rapid B-cell proliferation, whereas the FDC-rich light antigen. Indeed, displacement of these B cells by treat- zone functioned as the site for the selection of B-cell ment with endotoxins, such as lipopolysaccharide, was clones that express BCRs of the highest affinity follow- accompanied by impaired accumulation of immune ing somatic hypermutation. Recently, three independent complexes on the surface of FDCs in the follicles59,111,112. studies examining the spatio-temporal dynamics of Moreover, it has been shown that the accumulation of B cells have questioned the original model and the abso- IgM-containing immune complexes on FDCs was abro- lute ‘division of labour’ between the two zones of the gated in the absence of functional marginal-zone B cells. germinal centre102–104. Interestingly, each of these studies This suggests that marginal-zone B cells facilitate the showed that 6 days after antigen administration B cells adjuvant activity of IgM113. moved rapidly within the germinal centre, which indi- Marginal-zone B cells express complement receptors cated they did not make prolonged contacts with antigen (TABLE 1), and these may be important for their function presented on the surface of FDCs. It was therefore sug- in transporting antigen to FDCs. Indeed, early investi- gested that the mode of antigen recognition by B cells gations using cobra venom factor and antibodies against occurring during the later stages of an immune response C3 showed that the transport of immune complexes may operate differently to that observed during early from the marginal zone to the FDCs depends on com- antigen encounters. Indeed, these studies showed that ponents of the complement system85,89,114. In the absence germinal-centre B cells adopted an unusual morphology of CR2 expression by marginal-zone B cells, immune with many extended processes102–104. These processes complexes were associated predominantly with macro- may be responsible for mediating antigen internaliza- phages in the marginal zone, as the B cells failed to tion as the B cells migrate along the surface of the FDCs. transport antigen to the FDCs115. The mechanism by under antigen-limiting conditions, B cells expressing which marginal-zone B cells transport antigen from the Somatic hypermutation BCRs with higher affinity can accumulate more antigen marginal zone to the follicles was revealed by a recent (SHM). A unique mutation and consequently compete more effectively to recruit study involving the treatment of chimeric mice with the mechanism that is targeted specific T-cell help for their development, with only sphingosine 1-phosphate receptor 1 (s1PR1) antagonist to the variable regions of the highest affinity clones being selected for survival FTy720 (REF. 116). Marginal-zone B cells were found to rearranged immunoglobulin gene segments. Combined with in the germinal centre102,105. However, it is important to continually shuttle to and from the follicles in a process selection for B cells that note that CD4+ T cells reside exclusively within the light that depended on the expression of CXC-chemokine produce high-affinity antibody, zone, so the complete absence of functional segregation receptor 5 (CXCR5) and s1PR1, respectively. As mar- SHM leads to affinity in the germinal centre is unlikely. ginal-zone B cells can bind immune complexes through maturation of B cells in Antigen presentation by FDCs through binding of CR1 and CR2, this shuttling process could be the way germinal centres. immune complexes to FcRs or complement receptors may in which antigen is effectively delivered from the blood Cobra venom factor be important for the development of high-affinity antibody to FDCs. Interestingly, it has been postulated that the The complement-activating and long-lasting memory responses106. surprisingly, how- actual transfer of immune complexes from marginal- glycoprotein component of ever, the process of affinity maturation and the survival zone B cells to FDCs occurs through proteolysis of CR2 cobra venom, which is functionally analogous to the of memory B cells, although impaired, can occur in the on the surface of the marginal-zone B cells117. However, mammalian complement absence of detectable antigen deposition on FDCs107,108. it is not known whether marginal-zone B cells can pass factor C3b. This observation led to the hypothesis that in addition free antigen directly to follicular B cells. nATuRE REvIEws | Immunology vOluME 9 | jAnuARy 2009 | 23 © 2009 Macmillan Publishers Limited. All rights reserved
10. 10. REVIEWS similarly, it has been suggested that follicular B cells Conclusions and perspectives themselves function as antigen transporters in the lymph Overall, it is clear that B cells can respond rapidly to nodes and spleen89,118 (FIG. 3b). This activity does not antigenic stimulation through several mechanisms, and depend on antigen-specific recognition and therefore they also have a unique strategic role in the transport is mediated by receptors other than the BCR (TABLE 1). of antigen to FDCs in the germinal centre. This wide It has been proposed that antigen can be acquired by variety in potential antigen-presentation mechanisms is other follicular B cells in the absence of antigen-specific promoted by functional specialization within slOs and B cells64,67, and this may depend on the expression of provides invaluable flexibility in mounting appropriate complement receptors on the B-cell surface64. As FDCs immune responses to antigens. As such, the mechanism express higher levels of complement receptors than that is used to present a specific antigen can be effec- follicular B cells, it would be expected that they could tively tailored both to the antigen itself and to the way compete effectively with B cells for antigen binding 27. the antigen is delivered to the B cell. The predominance It remains to be determined whether other receptors of of cell-based strategies for the presentation of antigen to the innate immune system have a role in the transport B cells allows for extensive regulation and coordination of antigen by B cells within slOs. CD23+ mature B cells of the resulting immune responses. have in fact been shown to mediate the transport of In spite of significant recent progress in character- IgE-containing immune complexes into the follicle in a izing the sites and dynamics of antigen presentation BCR-independent manner 119. Although such a situation to B cells in vivo, some issues remain to be addressed. is unlikely to occur in physiological conditions, it does These include a definitive molecular description of the indicate that alternative receptors might be involved in mechanisms of antigen presentation to B cells, includ- antigen transport. ing the retention and internalization strategies that are a Splenic marginal-zone B cells transport antigen to FDCs b Follicular B cells in the lymph node transport antigen to FDCs S1Phi Immune Marginal zone Subcapsular sinus CXCL13low complex SCS macrophage C3 fragment CR Antigen FcR non-specific DC-SIGN BCR Marginal-zone B cell Follicular B cell ? ? Follicular dendritic cell S1Plow CXCL13hi Primary follicle Primary follicle Figure 3 | B cells mediate antigen transport to follicular dendritic cells using complement receptors. a | Marginal-zone B cells in the spleen can bind to immune complexes that contain antigen and are coated in complement fragments, using complement receptors (CR) in a manner that is independent of B-cell receptor (BCR) specificity. These Nature Reviews | Immunology marginal-zone B cells can shuttle to the follicular region, which is rich in CXC-chemokine ligand 13 (CXCL13), in a CXC- chemokine-receptor-5-dependent manner116. Follicular dendritic cells (FDCs) in the follicle, which express high levels of CR, can then compete for binding to antigen that is presented by marginal-zone B cells. The marginal-zone B cells then migrate back to the marginal zone, where there are high levels of sphingosine 1-phosphate (S1P), and this depends on their expression of the receptors for S1P1 and S1P3. b | Follicular B cells in the lymph node can bind to particulate antigen on the surface of subcapsular sinus (SCS) macrophages. This binding does not depend on the specificity of the BCR and is mediated by CRs. It has been suggested that these follicular B cells can then mediate the transport of antigen to FDCs, which express higher levels of CRs64,67. C3, complement component 3; DC-SIGN, DC-specific ICAM3-grabbing non-integrin; FcR, Fc receptor; ICAM3, intercellular adhesion molecule 3. 24 | jAnuARy 2009 | vOluME 9 © 2009 Macmillan Publishers Limited. All rights reserved
|
__label__1
| 0.541261
|
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.